Rare Disease Conditions Eligibility Criteria V1.6.0

Rare Disease Conditions Eligibility Criteria v1.6.0

Document Record ID Key Work stream Rare Diseases Programme Director Mark Caulfield Status Final Document Owner Richard Scott Version 1.0 Document Author Andrew Devereau, Richard Scott Version Date 16/12/2016 Ellen Thomas

Document History The controlled copy of this document is maintained in the Genomics England internal document management system. Any copies of this document held outside of that system, in whatever format (for example, paper, email attachment), are considered to have passed out of control and should be checked for currency and validity. This document is uncontrolled when printed.

Version History Version Date Description 0.1 14/12/2016 First draft from RC2 v1.6 catalogue 0.2 14/12/2016 Upgraded after review by Richard Scott 1.0 16/12/2016 Moved to 1.0 for distribution to NHSE

Reviewers This document must be reviewed by the following: Name Title Version Richard Scott Clinical Lead for Rare Disease 0.1

Approvers This document must be approved by the following: Name Responsibility Date Version Tom Fowler Director of Public Health 16/12/16 1.0 on behalf of Mark Caulfield Chief Scientist

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 1

Contents

Quick links page ...... 12 Introduction ...... 13 Purpose of this document ...... 13 Structure and background to eligibility statements ...... 13 Changes since the last release ...... 14 Rare Disease Conditions Eligibility Criteria ...... 19 Cardiovascular disorders (10950) ...... 19 Arteriopathies (33332) ...... 19 Familial cerebral small vessel disease (36469) ...... 19 Familial Hypercholesterolaemia (33666) ...... 21 Severe hypertriglyceridaemia (42185) ...... 23 Connective Tissues Disorders and Aortopathies (10951) ...... 25 Familial Thoracic Aortic Aneurysm Disease (11021) ...... 25 Cardiac arrhythmia (10952) ...... 27 Brugada syndrome (11022) ...... 27 Long QT syndrome (11023) ...... 29 Catecholaminergic Polymorphic Ventricular Tachycardia (11024) ...... 31 Unexplained sudden death in the young (38566) ...... 33 Idiopathic ventricular fibrillation (42161) ...... 35 Cardiomyopathy (10953) ...... 37 Arrhythmogenic Right Ventricular Cardiomyopathy (11025) ...... 37 Left Ventricular Noncompaction Cardiomyopathy (15044) ...... 39 Dilated Cardiomyopathy (31340) ...... 41 Dilated Cardiomyopathy and conduction defects (11027) ...... 43 Hypertrophic Cardiomyopathy (11028) ...... 45 Congenital heart disease (10954) ...... 47 Familial congenital heart disease (42212) ...... 47 Syndromic congenital heart disease (42213) ...... 49 Lymphatic disorders (33334) ...... 50

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 2

Meige disease (34328) ...... 50 Milroy disease (37604) ...... 52 Lymphoedema distichiasis (37612) ...... 53 Ciliopathies (10963) ...... 54 Congenital malformations caused by ciliopathies (15091) ...... 54 Bardet-Biedl Syndrome (11046) ...... 54 Joubert syndrome (36478) ...... 56 Rare multisystem ciliopathy disorders (36488) ...... 57 Respiratory ciliopathies (15092) ...... 59 Primary ciliary dyskinesia (11047)...... 59 Non-CF bronchiectasis (11048) ...... 61 Dermatological disorders (10956) ...... 63 Atopy (15084) ...... 63 Severe multi-system atopic disease with high IgE (15085) ...... 63 Autoimmune skin disorders (33336) ...... 65 Generalised pustular psoriasis (33646) ...... 65 Ectodermal dysplasias (33338)...... 66 Ectodermal dysplasia without a known gene mutation (33699) ...... 66 Ichthyoses (33340) ...... 67 Autosomal recessive congenital ichthyosis (33700) ...... 67 Keratodermas (33342) ...... 69 Palmoplantar keratoderma and erythrokeratodermas (33701) ...... 69 Familial disseminated superficial actinic porokeratosis (37644) ...... 71 Neurocutaneous disorders (33344) ...... 72 Undiagnosed neurocutaneous disorders (33686) ...... 72 Skin adnexa disorders (36587) ...... 74 Familial cicatricial alopecia (36588) ...... 74 Familial hidradenitis suppurativa (41844) ...... 75 Non-syndromic hypotrichosis (36849) ...... 77 Skin fragility disorders (33346) ...... 78 Epidermolysis bullosa (33684) ...... 78 Peeling skin syndrome (36540) ...... 79

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 3

Sun-exposure related conditions (10958) ...... 80 Erythropoietic protoporphyria, mild variant (11037) ...... 80 Hydroa vacciniforme (15083) ...... 82 Dysmorphic and congenital abnormality syndromes (10959) ...... 83 Kabuki (28664) ...... 83 Kabuki syndrome (10960) ...... 83 RASopathies (10961) ...... 86 Noonan syndrome (11039) ...... 86 Noonan syndrome plus other features (11040) ...... 88 Cardio-facio-cutaneous syndrome (11041) ...... 90 LEOPARD syndrome (11042) ...... 92 Costello syndrome (11043) ...... 94 Legius syndrome (11044) ...... 96 Balanced translocations (10962) ...... 98 Balanced translocations with an unusual phenotype (11045) ...... 98 Limb disorders (15087) ...... 99 VACTERL-like phenotypes (10964) ...... 99 DNA repair disorders (10965) ...... 101 Cockayne syndrome (36497) ...... 101 Non-Fanconi anaemia (11050) ...... 103 Xeroderma Pigmentosum-like disorders (15089) ...... 105 Primary Microcephaly - Microcephalic Dwarfism Spectrum (36505) ...... 106 Autophagy disorders (10966) ...... 107 Vici Syndrome and other autophagy disorders (11051) ...... 107 Dysmorphic disorders (36595) ...... 109 Coarse facial features including Coffin-Siris-like disorders (36596) ...... 109 Familial non-syndromic cleft lip and or familial cleft palate (37565) ...... 111 Syndromic cleft lip and or cleft palate (37573) ...... 113 PHACE(S) syndrome (37578) ...... 115 Radial dysplasia (37636) ...... 116 Fetal disorders (38586) ...... 118 Fetal hydrops (37586) ...... 118

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 4

Unexplained monogenic fetal disorders (38665) ...... 120 Endocrine disorders (10967) ...... 121 Adrenal disorders (10969) ...... 121 Congenital adrenal hypoplasia (11053) ...... 121 Disorders of calcium homeostasis (10970) ...... 123 Familial or syndromic hypoparathyroidism (11054) ...... 123 Gonadal and sex development disorders (36923) ...... 125 Disorders of sex development (36852) ...... 125 Early onset familial premature ovarian insufficiency (36851) ...... 127 Growth hormone disorders (10971) ...... 129 IUGR and IGF abnormalities (11057) ...... 129 Hypothalamic and pituitary disorders (42204) ...... 131 Idiopathic hypogonadotropic hypogonadism (41827) ...... 131 Obesity syndromes (10973) ...... 133 Significant early-onset obesity with or without other endocrine features and short stature (11060) ...... 133 Rare subtypes of diabetes (15099) ...... 134 Familial young-onset non-insulin-dependent diabetes (15103) ...... 134 Hyperinsulinism (15105)...... 136 Neonatal diabetes (diagnosed less than 6 months) (30553) ...... 137 Diabetes with additional phenotypes suggestive of a monogenic aetiology (30559) ...... 138 Insulin resistance (including lipodystrophy) (30561) ...... 138 Multi-organ autoimmune diabetes (30563) ...... 140 Thyroid disorders (42208) ...... 141 Congenital hypothyroidism (41908) ...... 141 Resistance to thyroid hormone (41916)...... 143 Gastroenterological disorders (38581)...... 144 Gastrointestinal disorders (38582) ...... 144 Infantile enterocolitis and monogenic inflammatory bowel disease (37490) ...... 144 Gastrointestinal epithelial barrier disorders (37772) ...... 146 Non-syndromic familial congenital anorectal malformations (41868) ...... 148 Early onset or familial intestinal pseudo obstruction (41876) ...... 150 Growth disorders (10974) ...... 152

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 5

Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders (10975) ...... 152 Classical Beckwith-Wiedemann syndrome (11063) ...... 152 Atypical Beckwith-Wiedemann syndrome (11064) ...... 154 Simpson-Golabi-Behmel syndrome (11065) ...... 156 Sotos syndrome (11066) ...... 157 Weaver syndrome (11067) ...... 158 Growth restriction (38585) ...... 159 Silver Russell syndrome (37553) ...... 159 Haematological disorders (10977) ...... 161 Anaemias and red cell disorders (10979) ...... 161 Early onset pancytopenia and red cell disorders (11073) ...... 161 Congenital anaemias (11075) ...... 163 Apparent aplastic anaemia or paroxysmal nocturnal haemoglobinuria (33681) ...... 164 Immune dysregulation disorders (42205) ...... 166 Familial haemophagocytic lymphohistiocytic disorders (41836) ...... 166 Primary immunodeficiency disorders (10978)...... 168 A- or hypo-gammaglobulinaemia (11068) ...... 168 Agranulocytosis (11069) ...... 170 Combined B and T cell defect (11072) ...... 171 Congenital neutropaenia (11070) ...... 172 Inherited complement deficiency (33953) ...... 173 SCID (11071) ...... 174 Hearing and ear disorders (10980) ...... 175 Non-syndromic hearing loss (10981) ...... 175 Congenital hearing impairment (11076) ...... 175 Auditory Neuropathy Spectrum Disorder (30607) ...... 177 Autosomal dominant deafness (36848) ...... 179 Deafness and congenital structural abnormalities (10982) ...... 181 Bilateral microtia (11077) ...... 181 Familial hemifacial microsomia (37649) ...... 183 Ear malformations with hearing impairment (37657) ...... 185 Infectious diseases (42209) ...... 187

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 6

Bacterial disorders (42210) ...... 187 Disseminated non-tuberculous mycobacterial infection (41932) ...... 187 Metabolic disorders (10983) ...... 189 Specific metabolic abnormalities (10984) ...... 189 Ketotic hypoglycaemia (11080) ...... 189 Lactic acidosis (11081) ...... 191 Cerebral folate deficiency (11083) ...... 192 Undiagnosed metabolic disorders (37620) ...... 193 Congential disorders of glycosylation (37628) ...... 194 Urea Cycle disorders (15108) ...... 196 Hyperammonaemia (11079) ...... 196 Lysosomal storage disorders (10985) ...... 198 Mucopolysaccharideosis, Gaucher, Fabry (11084) ...... 198 Mitochondrial (10986) ...... 200 Mitochondrial disorders (11085) ...... 200 Peroxisomal disorders (10987) ...... 202 Peroxisomal biogenesis disorders (11086) ...... 202 Other peroxisomal disorders (15109) ...... 204 Disorders of extremely low weight , severe familial anorexia (15110) ...... 205 Severe familial anorexia (29278) ...... 205 Neurology and neurodevelopmental disorders (10988) ...... 207 Motor Disorders of the CNS (10989) ...... 207 Cerebellar hypoplasia (36512) ...... 207 Hereditary ataxia (11087) ...... 209 Early onset dystonia (11088) ...... 211 Hereditary spastic paraplegia (11089) ...... 213 Neurotransmitter disorders (37779) ...... 215 Structural basal ganglia disorders (37786) ...... 217 Inherited Epilepsy Syndromes (10990) ...... 218 Genetic Epilepsies with Febrile Seizures Plus (11091) ...... 218 Familial Genetic Generalised Epilepsies (11092) ...... 220 Familial Focal Epilepsies (11093) ...... 221

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 7

Epileptic encephalopathy (11094) ...... 222 Epilepsy plus other features (41924) ...... 223 Motor and Sensory Disorders of the PNS (10991)...... 225 Charcot-Marie-Tooth disease (15111) ...... 225 Paediatric motor neuronopathies (11099) ...... 227 Neurodegenerative disorders (10992) ...... 228 Early onset and familial Parkinson's Disease (11100) ...... 228 Complex Parkinsonism (includes pallido-pyramidal syndromes) (15112) ...... 230 Early onset dementia (encompassing fronto-temporal dementia and prion disease) (15113) ...... 232 Amyotrophic lateral sclerosis or motor neuron disease (15114) ...... 234 Neurodevelopmental disorders (10993) ...... 236 Classical tuberous sclerosis (11101) ...... 236 Intellectual disability (11102) ...... 238 Holoprosencephaly (36519) ...... 240 Rhomboencephalosynapsis (36603) ...... 242 Malformations of cortical development (36526) ...... 243 Fetal structural CNS abnormalities (36850) ...... 245 Neuromuscular disorders (10994) ...... 247 Congenital muscular dystrophy (15135) ...... 247 Congenital myopathy (11103) ...... 248 Congenital myaesthenia (15136) ...... 250 Rhabdomyolysis and metabolic muscle disorders (15137) ...... 251 Distal myopathies (11104) ...... 253 Arthrogryposis (15138) ...... 255 Limb girdle muscular dystrophy (11106) ...... 257 Channelopathies (11097) ...... 259 Skeletal Muscle Channelopathies (15139) ...... 259 Brain channelopathy (15140) ...... 261 Sleep disorders (10995) ...... 263 Kleine-Levin syndrome and other inherited sleep disorders (11108) ...... 263 Cerebrovascular disorders (36610) ...... 265 Moyamoya disease (36611) ...... 265

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 8

Vein of Galen malformation (42174) ...... 266 Parenchymal brain disorders (36618) ...... 267 Intracerebral calcification disorders (36619) ...... 267 White matter disorders (36626) ...... 268 Inherited white matter disorders (36627) ...... 268 Ophthalmological disorders (10996) ...... 270 Anterior segment abnormalities (10997) ...... 270 Corneal abnormalities (11110) ...... 270 Glaucoma (developmental) (11111) ...... 272 Cataracts (11112) ...... 274 Posterior segment abnormalities (10998)...... 275 Inherited optic neuropathies (11114)...... 275 Rod-cone dystrophy (29268) ...... 277 Rod Dysfunction Syndrome (29269) ...... 278 Cone Dysfunction Syndrome (29270) ...... 279 Inherited macular dystrophy (29271) ...... 280 Leber Congenital Amaurosis or Early-Onset Severe Retinal Dystrophy (29272) ...... 282 Developmental macular and foveal dystrophy (29273) ...... 283 Familial exudative vitreoretinopathy (41900) ...... 285 Ocular malformations (10999) ...... 287 Anophthalmia or microphthamia (11115) ...... 287 Ocular coloboma (15141) ...... 289 Ocular movement disorders (33350) ...... 290 Infantile nystagmus (33662) ...... 290 Renal and urinary tract disorders (11000)...... 292 Syndromes with prominent renal abnormalities (11001) ...... 292 Proteinuric renal disease (30732) ...... 292 Familial haematuria (30733) ...... 294 Atypical haemolytic uraemic syndrome (33489) ...... 296 Structural renal and urinary tract disease (11003) ...... 297 Cystic kidney disease (11120) ...... 297 Congenital Anomaly of the Kidneys and Urinary Tract (CAKUT) (29277) ...... 299

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 9

Disorders of function (11004) ...... 301 Renal tubular acidosis (11123) ...... 301 Renal tract calcification (or Nephrolithiasis or nephrocalcinosis) (11124) ...... 303 Extreme early-onset hypertension (15142) ...... 305 Unexplained kidney failure in young people (36855) ...... 306 Respiratory disorders (33353) ...... 308 Interstitial lung disorders (33354) ...... 308 Familial pulmonary fibrosis (33671) ...... 308 Vascular lung disorders (33355) ...... 310 Hereditary haemorrhagic telangiectasia (33674) ...... 310 Familial and multiple pulmonary arteriovenous malformations (33677) ...... 312 Structural lung disorders (42203) ...... 314 Familial primary spontaneous pneumothorax (41819) ...... 314 Rheumatological disorders (11009) ...... 316 Multi-system inflammatory or autoimmune disorders (11008) ...... 316 Periodic fever syndromes and amyloidosis (11127) ...... 316 Juvenile dermatomyositis (29219) ...... 318 Connective tissues disorders (36930) ...... 319 Kyphoscoliotic Ehlers-Danlos syndrome (36853) ...... 319 Classical Ehlers-Danlos Syndrome (41860) ...... 321 Skeletal disorders (11005) ...... 322 Skeletal dysplasias (11007) ...... 322 Multiple Epiphyseal Dysplasia (11125) ...... 322 Chondrodysplasia punctata (15143) ...... 324 Thoracic dystrophies (11126) ...... 326 Stickler syndrome (11129) ...... 327 Osteogenesis imperfecta (30627) ...... 329 Unexplained skeletal dysplasia (36854) ...... 331 Craniosynostosis (30775)...... 332 Craniosynostosis syndromes (11006) ...... 332 Choanal anomalies (31500) ...... 334 Choanal atresia (11078) ...... 334

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 10

Tumour syndromes (11012) ...... 336 Breast and endocrine (11013)...... 336 Familial breast cancer (11131) ...... 336 Multiple endocrine tumours (11132) ...... 338 Neuro-endocrine Tumours- PCC and PGL (11133) ...... 340 Parathyroid cancer (30611) ...... 341 Inherited non-medullary thyroid cancer (41884) ...... 342 GI tract (11014) ...... 344 Familial colon cancer (11135) ...... 344 Multiple bowel polyps (30615) ...... 346 Peutz-Jeghers syndrome (36533) ...... 348 Muscle and nerve (11015) ...... 350 Familial rhabdomyosarcoma or sarcoma (11138) ...... 350 Familial tumour syndromes of the central and peripheral nervous system (30619) ...... 352 Neurofibromatosis Type 1 (38874) ...... 354 Skin (11016) ...... 356 Genodermatoses with malignancies (30623) ...... 356 Young onset tumour syndromes (30781) ...... 358 Paediatric congenital malformation-dysmorphism-tumour syndromes (30686) ...... 358 Exceptionally young adult onset cancer (41892) ...... 360 Multiple Primaries (30782) ...... 362 Multiple Tumours (30685) ...... 362 Ultra-rare disorders (30783) ...... 364 Undescribed disorders (30784) ...... 364 Ultra-rare undescribed monogenic disorders (30785) ...... 364 Multi-system groups (38589) ...... 366 Neonatal or paediatric intensive care admission with a likely monogenic disease (38558) .. 366 Single autosomal recessive mutation in rare disease (38672) ...... 368 Undiagnosed monogenic disorder seen in a specialist genetics clinic (42193)...... 369

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 11

Quick links page

Cardiovascular disorders (10950) Ciliopathies (10963) Dermatological disorders (10956) Dysmorphic and congenital abnormality syndromes (10959) Endocrine disorders (10967) Gastroenterological disorders (38581) Growth disorders (10974) Haematological disorders (10977) Hearing and ear disorders (10980) Infectious diseases (42209) Metabolic disorders (10983) Neurology and neurodevelopmental disorders (10988) Ophthalmological disorders (10996) Renal and urinary tract disorders (11000) Respiratory disorders (33353) Rheumatological disorders (11009) Skeletal disorders (11005) Tumour syndromes (11012) Ultra-rare disorders (30783)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 12

Introduction

Purpose of this document

The aim of this document is to provide an up-to-date list of eligibility criteria for conditions approved for recruitment within the Genomics England Rare Diseases Programme.

Structure and background to eligibility statements

For each disease listed we provide an “eligibility statement” composed of the following key information:

1. Inclusion criteria – the clinical features, characteristics or investigations that probands with a given disease must have in order to be eligible for recruitment. 2. Exclusion criteria - the clinical features, characteristics or investigation findings that participants with a given disease must not have in order to be eligible for recruitment. 3. Prior genetic testing – this sets out both in general terms, and where appropriate more specifically, the genetic testing which participants with a given disease must have performed prior to recruitment.

Each eligibility statement has been informed by at least one clinician specialising in the field and incorporates comments provided during the consultation period with Genomic Medicine Centres. Therefore, we would like to take this opportunity to thank this community for providing their expertise and understanding of complex disorders so generously.

Given the rapid progress in the understanding of rare diseases worldwide, it is important that the eligibility statements continue to be reviewed and developed over time in light of new discoveries and changes in clinical practice. Therefore we will continue our engagement with the clinical community throughout the lifetime of the project.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 13

Changes since the last release

Since the release of version 1.5 of this document a number of changes have been made.

New and revised diseases

New categories, subcategories and diseases have been created, or their names revised, as shown in the table below. In total 21 new Diseases have been added and 6 replaced. One new disorder Category and five new Subcategories have been created to accommodate these new diseases, and two Subcategories and one Disease have been renamed. Added or changed items are highlighted in yellow, with details of the change shown in the Comments column:

Category Subcategory Disease Comments Cardiovascular Arteriopathies (33332) Severe hypertriglyceridaemia Disease added disorders (10950) (42185) Cardiac arrhythmia Idiopathic ventricular Disease added (10952) fibrillation (42161) Congenital heart Familial congenital heart New diseases disease (10954) disease (42212) Familial congenital heart disease and Syndromic congenital heart disease replace: Fallots tetralogy (11029) Hypoplastic Left Heart Syndrome (11030) Pulmonary atresia (11031) Transposition of the great vessels (11032) Left Ventricular Outflow Tract obstruction disorders (11033)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 14

Isomerism and laterality disorders (11034) Syndromic congenital heart New diseases disease (42213) Familial congenital heart disease and Syndromic congenital heart disease replace: Fallots tetralogy (11029) Hypoplastic Left Heart Syndrome (11030) Pulmonary atresia (11031) Transposition of the great vessels (11032) Left Ventricular Outflow Tract obstruction disorders (11033) Isomerism and laterality disorders (11034) Dermatological Skin adnexa disorders Familial hidradenitis Subcategory ‘Skin disorders (10956) (36587) suppurativa (41844) adnexa disorders’ is renamed from ‘Hair Disorders (Skin adnexa disorders)’ and Disease ‘Familial hidradenitis suppurativa (41844)’ added Endocrine disorders Hypothalamic and Idiopathic hypogonadotropic Subcategory (10967) pituitary disorders hypogonadism (41827) ‘Hypothalamic and (42204) pituitary disorders (42204)’ and Disease ‘Idiopathic

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 15

hypogonadotropic hypogonadism (41827)’ added Thyroid disorders Congenital hypothyroidism Subcategory (42208) (41908) ‘Thyroid disorders (42208)’ and Disease ‘Congenital hypothyroidism (41908)’ added Resistance to thyroid hormone Disease added (41916) Gastroenterological Gastrointestinal Non-syndromic familial Disease added disorders (38581) disorders (38582) congenital anorectal malformations (41868) Early onset or familial Disease added intestinal pseudo obstruction (41876) Haematological Immune dysregulation Familial haemophagocytic Subcategory disorders (10977) disorders (42205) lymphohistiocytic disorders ‘Immune (41836) dysregulation disorders (42205)’ and Disease ‘Familial haemophagocytic lymphohistiocytic disorders (41836)’ added Infectious diseases Bacterial disorders Disseminated non-tuberculous Category ‘Infectious (42209) (42210) mycobacterial infection diseases (42209)’ (41932) Subcategory ‘Bacterial disorders (42210)’ and Disease ‘Disseminated non- tuberculous mycobacterial

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 16

infection (41932)’ added Neurology and Inherited Epilepsy Epilepsy plus other features Disease added neurodevelopmental Syndromes (10990) (41924) disorders (10988) Cerebrovascular Vein of Galen malformation Disease added disorders (36610) (42174) Ophthalmological Posterior segment Familial exudative Disease added disorders (10996) abnormalities (10998) vitreoretinopathy (41900) Respiratory disorders Structural lung Familial primary spontaneous Subcategory (33353) disorders (42203) pneumothorax (41819) ‘Structural lung disorders (42203)’ and Disease ‘Familial primary spontaneous pneumothorax (41819)’ added Rheumatological Connective tissues Classical Ehlers-Danlos Disease added disorders (11009) disorders (36930) Syndrome (41860) Tumour syndromes Breast and endocrine Inherited non-medullary Disease added (11012) (11013) thyroid cancer (41884) Young onset tumour Paediatric congenital Subcategory ‘Young syndromes (30781) malformation-dysmorphism- onset tumour tumour syndromes (30686) syndromes (30781)’ renamed from ‘Childhood Tumours (Young onset tumours)’, Disease ‘Paediatric congenital malformation- dysmorphism- tumour syndromes (30686)’ revised from ‘Paediatric congenital

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 17

malformation- dysmorphism- tumour sydromes’ to correct a typo. Exceptionally young adult Disease added onset cancer (41892) Ultra-rare disorders Undescribed disorders Ultra-rare undescribed Disease added (30783) (30784) monogenic disorders (30785) Multi-system groups Undiagnosed monogenic Disease added (38589) disorder seen in a specialist genetics clinic (42193)

Changes to eligibility criteria

New eligibility criteria have been created for the new diseases listed above. Changes have been made to the eligibility criteria in 11 previously developed diseases: 1. Classical Beckwith-Wiedemann syndrome (11063) 2. Atypical Beckwith-Wiedemann syndrome (11064) 3. Silver Russell syndrome (37553) 4. Congenital hearing impairment (11076) 5. Early onset dystonia (11088) 6. Infantile nystagmus (33662) 7. Hereditary haemorrhagic telangiectasia (33674) 8. Familial and multiple pulmonary arteriovenous malformations (33677) 9. Familial breast cancer (11131) 10. Multiple endocrine tumours (11132) 11. Familial Tumours Syndromes of the central and peripheral Nervous system (30619)

Minor changes have been made to some text symbols in the clinical inclusion and/or exclusion criteria in the following existing diseases. These do not change the interpretation of the criteria: 1. Classical tuberous sclerosis (11101) 2. Neuro-endocrine Tumours- PCC and PGL (11133) 3. Familial colon cancer (11135) 4. Multiple bowel polyps (30615) 5. Familial rhabdomyosarcoma or sarcoma (11138) 6. Genodermatoses with malignancies (30623)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 18

Rare Disease Conditions Eligibility Criteria

Cardiovascular disorders (10950)

Arteriopathies (33332)

Familial cerebral small vessel disease (36469)

Familial cerebral small vessel disease eligibility (36473)

Level 3 Title Arteriopathies (33332)

Level 4 Title Familial cerebral small vessel disease (36469)

Eligibility Statement Familial cerebral small vessel disease inclusion criteria (36473) • Clinical features consistent with cerebral small vessel disease: either lacunar stroke or vascular cognitive impairment/dementia, AND • MRI confirmed evidence of cerebral small vessel disease as evidenced by; multiple lacunar infarcts and/or confluent white matter hyperintensities, AND • Early onset cerebral SVD (<60 years) without cardiovascular risk factors or affected first degree family member

In other cases, unaffected individuals should not be recruited. Recruitment in such families should favour multiplex families over single isolated cases. These singleton recruits will not contribute to the overall singleton monitoring metrics applied to GMCs.

Familial cerebral small vessel disease exclusion criteria (36473) • Causes of white matter disease other than cerebral small vessel disease (e.g. multiple sclerosis, vasculitis,

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 19

leukodystrophy). • Cases with NOTCH3 mutations

Prior genetic testing guidance (36473) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

PLEASE NOTE: The sensitivity of WGS compared to current diagnostic genetic testing has not yet been established. It is therefore important that tests which are clinically indicated under local standard practice continue to be carried out.

Familial cerebral small vessel disease prior genetic testing genes (36473) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: NOTCH3

Closing statement (36473) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 20

Familial Hypercholesterolaemia (33666)

Familial Hypercholesterolaemia eligibility (33440)

Level 3 Title Arteriopathies (33332)

Level 4 Title Familial Hypercholesterolaemia (33666)

Eligibility Statement Familial Hypercholesterolaemia inclusion criteria (33440) Lipid levels either pre-treatment or highest on treatment: • Simon Broome criteria ‘definite familial hypercholesterolaemia’: • Abnormal lipids: -Total cholesterol > 6.7 mmol/l (260 mg/dl), or LDL cholesterol above 4.0 mmol/l in a child < 16 years, OR -Total cholesterol >7.5 mmol/l (290 mg/dl), or LDL cholesterol above 4.9 mmol/l (190 mg/dl) in an adult AND -Tendon xanthomas (TX) in patient, or in 1st degree relative (parent, sibling, child), or in 2nd degree relative (grandparent, uncle, aunt) OR • Abnormal lipids: -Total cholesterol > 6.7 mmol/l (260 mg/dl), or LDL cholesterol above 4.0 mmol/l in a child < 16 years, OR -Total cholesterol >8.5 mmol/l, or LDL cholesterol above 5.5 mmol/l in an adult AND - Family history of myocardial infarction below age of 50 in 2nd degree relative or below age 60 in 1st degree relative, OR - Family history of raised cholesterol: >7.5 mmol/l in adult 1st or 2nd degree relative or > 6.7 mmol/l in child or sibling under 16 AND • Polygenic risk 12-SNP gene score in the bottom two quartiles

Familial Hypercholesterolaemia exclusion criteria (33440) • Secondary causes of elevated LDL-C. Patients will only be eligible who have elevated LDL-C on measures taken on a fasting blood sample and after secondary causes of hyperlipidaemia have been excluded. • Recessive inheritance. Families showing a recessive pattern of inheritance will not be recruited

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 21

• Individuals with a fasting plasma Triglyceride level of over 2.5mmol/l will be excluded.

Prior genetic testing guidance (33440) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Familial Hypercholesterolaemia prior genetic testing genes (33440) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: LDLR, APOB and PCSK9 Polygenic risk 12-SNP gene score

Closing statement (33440) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 22

Severe hypertriglyceridaemia (42185)

Severe hypertriglyceridaemia eligibility (42186)

Level 3 Title Arteriopathies (33332)

Level 4 Title Severe hypertriglyceridaemia (42185)

Eligibility Statement Severe hypertriglyceridaemia inclusion criteria (42186) Triglycerides >20mmol/L AND one of Asymptomatic, OR Acute pancreatitis event, OR Eruptive xanthomata

Severe hypertriglyceridaemia exclusion criteria (42186) Excess alcohol intake ( >30 units/week) Uncontrolled diabetes ( HbA1c >8%) Known lipodystrophy syndrome- genetic or acquired Known mitochondrial myopathy Use of anti-retroviral drug therapies

Prior genetic testing guidance (42186) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 23

Severe hypertriglyceridaemia prior genetic testing genes (42186) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: LPL, APOA5, APOC2, GPIHBP1, LMF1

Closing statement (42186) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 24

Connective Tissues Disorders and Aortopathies (10951)

Familial Thoracic Aortic Aneurysm Disease (11021)

Familial Thoracic Aortic Aneurysm Disease eligibility (29317)

Level 3 Title Connective Tissues Disorders and Aortopathies (10951)

Level 4 Title Familial Thoracic Aortic Aneurysm Disease (11021)

Eligibility Relevant Diseases: Statement - Familial Thoracic Aortic Aneurysm and dissection - Thoracic aortopathy < 50 years with no other established risk factors - Clinically diagnosed Marfan syndrome with no FBN1 mutation - Loeys-Dietz syndrome and Loeys-Dietz syndrome like conditions - Mutation negative Congenital Contractural Arachnodactyly (Beals syndrome)

Familial Thoracic Aortic Aneurysm Disease inclusion criteria (Conditions) (29317) - patients suspected to have the above conditions Individuals with severe or syndromic disease should be recruited according to standard guidance, typically as trios. Disease status of apparently unaffected participants should be determined according to standard clinical practice to detect cryptic disease. In other cases, unaffected individuals should not be recruited. Recruitment in such families should favour multiplex families over single isolated cases. These singleton recruits will not contribute to the overall singleton monitoring metrics applied to GMCs.

Familial Thoracic Aortic Aneurysm Disease exclusion criteria: (29317) - Sporadic thoracic aortopathies with risk factors - Family history with no affected proband to test

Prior genetic testing guidance (29317) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Familial Thoracic Aortic Aneurysm Disease prior genetic testing genes: (29317)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 25

Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - Loeys-Dietz syndrome TGFBR1 and TGFBR2 - Marfan Syndrome FBN1 - Congenital Contractural Arachnodactyly FBN2 - Isolated familial thoracic aortic aneurysms and dissection - ACTA2

Closing statement (29317) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 26

Cardiac arrhythmia (10952)

Brugada syndrome (11022)

Brugada eligibility (29319)

Level 3 Title Cardiac arrhythmia (10952)

Level 4 Title Brugada syndrome (11022)

Eligibility Relevant diseases: Statement - Brugada syndrome

Brugada inclusion criteria (clinical diagnosis) (29319) Brugada syndrome diagnosed according to criteria*: - ST segment elevation with type I morphology>= 2 mm in >= 1 lead among the right precordial leads V1,V2 positioned in the 2nd, 3rd, or 4th intercostal space occurring spontaneously.

OR - a type I ECG morphology as above following a provocative drug test with intravenous administration of Class I antiarrhythmic drugs.

AND one or more of the three criteria below: a family history of: - premature sudden death (<40 years old) or autopsy negative sudden death <65 years old: the sudden arrhythmic death syndrome (SADS)

AND/OR - other relatives with a diagnosis of BrS (spontaneous or drug-induced; symptomatic or asymptomatic)

AND/OR - survivor of cardiac arrest with a spontaneous type I ECG pattern (constant or intermittent), to be recruited as a trio with parents who have been tested for BrS with normal results * Heart Rhythm Society/European Heart Rhythm Association

Individuals with severe or syndromic disease should be recruited according to standard guidance, typically as trios. Disease status of apparently unaffected participants should be determined according to standard clinical practice to detect cryptic disease. In other cases, unaffected individuals should not be recruited. Recruitment in such families should favour multiplex families over single isolated cases. These singleton recruits will not contribute to the overall singleton monitoring metrics applied to GMCs.

Brugada exclusion criteria (unclear diagnosis) (29319) - Unclear diagnosis or history suggestive of a non-genetic cause

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 27

- Any Brugada syndrome mutation positive (if clearly pathogenic)

Prior genetic testing guidance (29319) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Brugada prior genetic testing genes (29319) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: SCN5A

Closing statement (29319) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 28

Long QT syndrome (11023)

Long QT Syndrome eligibility (29335)

Level 3 Title Cardiac arrhythmia (10952)

Level 4 Title Long QT syndrome (11023)

Eligibility Relevant diseases: Statement - Long QT syndrome

Long QT inclusion criteria (29335) LQTS diagnosed according to criteria*:

- In the presence of an LQTS risk score >= 3.5 in the absence of a secondary cause for QT prolongation

AND/OR

- In the presence of a corrected QT interval for heart rate using Bazett’s formula (QTc) >= 500ms in repeated 12 lead electrocardiogram (ECG) and in the absence of a secondary cause for QT prolongation.

AND/OR

- In the presence of a QTc between 480 and 499ms in repeated 12-lead ECGs in a patient with unexplained syncope in the absence of a secondary cause for QT prolongation in the absence of a pathogenic mutation.

AND either one of the two criteria below:

- A family history for LQTS with other affected family DNA and phenotype available (at least three over three generations) for linkage studies.

- Trio of unaffected parents and severely affected child available (sporadic or recessive)

* Heart Rhythm Society/European Heart Rhythm Association

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 29

should favour multiplex families over single isolated cases. These singleton recruits will not contribute to the overall singleton monitoring metrics applied to GMCs.

Long QT exclusion criteria (29335) - Unclear diagnosis or history suggestive of a non-genetic cause - Any LQTS mutation positive (if clearly pathogenic)

Prior genetic testing guidance (29335) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Long QT syndrome prior genetic testing genes (29335) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - KCNQ1, KCNH2 and SCN5A

Closing statement (29335) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 30

Catecholaminergic Polymorphic Ventricular Tachycardia (11024)

Catecholaminergic Polymorphic Ventricular Tachycardia eligibility (29337)

Level 3 Title Cardiac arrhythmia (10952)

Level 4 Title Catecholaminergic Polymorphic Ventricular Tachycardia (11024)

Eligibility Relevant diseases: Statement - Catecholaminergic polymorphic ventricular tachycardia (CPVT)

Catecholaminergic Polymorphic Ventricular Tachycardia inclusion criteria (29337) CPVT diagnosed according to criteria*:

- In the presence of a structurally normal heart, normal ECG, and unexplained exercise or catecholamine induced bidirectional VT or polymorphic ventricular premature beats (VPBs) or VT in an individual younger than 40 years.

- In the presence of a structurally normal heart and coronary arteries, normal ECG, and unexplained exercise or catecholamine-induced bidirectional VT or polymorphic VPBs or VT in an individual older than 40 years.

AND either one of the two criteria below:

- A family history for CPVT with other affected family DNA and phenotype available (at least three over three generations) for linkage studies.

- Trio of unaffected parents and severely affected child available (sporadic or recessive)

* Heart Rhythm Society/European Heart Rhythm Association

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 31

metrics applied to GMCs.

Catecholaminergic Polymorphic Ventricular Tachycardia exclusion criteria (29337) - Unclear diagnosis or history suggestive of a non-genetic cause - Any CPVT mutation positive (if clearly pathogenic)

Prior genetic testing guidance (29337) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Catecholaminergic Polymorphic Ventricular Tachycardia prior genetic testing genes (29337) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: CPVT, RYR2

Closing statement (29337) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 32

Unexplained sudden death in the young (38566)

Unexplained sudden death in the young eligibility (38569)

Level 3 Title Cardiac arrhythmia (10952)

Level 4 Title Unexplained sudden death in the young (38566)

Eligibility Statement Unexplained sudden death in the young inclusion criteria (38569) • Sudden death at age less than or equal to 40 (including Sudden Infant Death Syndrome), AND • No diagnosis established on post mortem examination, AND • Absence of a pre-existing condition to explain the death. • Parents should be recruited under this category in paediatric cases if available • In adult cases the deceased individual should be recruited as a singleton; if surviving relatives have a phenotype which points to a particular condition, they should be the focus of further investigation or recruitment to the programme. • Surviving relatives must be available to provide appropriate consent.

Unexplained sudden death in the young exclusion criteria (38569) • Death in the context of a known diagnosed disease or accident • Cause of death determined by post mortem examination • No post mortem examination carried out • No DNA or frozen tissue stored at post mortem.

Prior genetic testing guidance (38569) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Unexplained sudden death in the young prior genetic testing genes (38569) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: No genes listed

Closing statement (38569)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 33

These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 34

Idiopathic ventricular fibrillation (42161)

Idiopathic ventricular fibrillation eligibility (42162)

Level 3 Title Cardiac arrhythmia (10952)

Level 4 Title Idiopathic ventricular fibrillation (42161)

Eligibility Statement Idiopathic ventricular fibrillation inclusion criteria (42162) Proband with unexplained documented VF cardiac arrest despite comprehensive clinical evaluation

PLUS EITHER

A. Juvenile sporadic VF (Age 1-18 years). Recruitment should be as trios.

B. Idiopathic VF aged 1-45 years with family history of idiopathic VF or SADS in a first, second or third degree relative. In category B, unaffected individuals should not be recruited. Recruitment in such families should favour multiplex families over single isolated cases. These singleton recruits will not contribute to the overall singleton monitoring metrics applied to GMCs.

Disease status of apparently unaffected participants should be determined according to standard clinical practice to detect cryptic disease.

Idiopathic ventricular fibrillation exclusion criteria (42162) Age of disease <1 or >45y in proband or qualifying relative, OR Known inherited arrhythmogenic disorder identified on clinical evaluation

Prior genetic testing guidance (42162) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 35

Idiopathic ventricular fibrillation prior genetic testing genes (42162) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: No genes specified

Closing statement (42162) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 36

Cardiomyopathy (10953)

Arrhythmogenic Right Ventricular Cardiomyopathy (11025)

Arrhythmogenic Right Ventricular Cardiomyopathy eligibility (29339)

Level 3 Title Cardiomyopathy (10953)

Level 4 Title Arrhythmogenic Right Ventricular Cardiomyopathy (11025)

Eligibility Relevant diseases: Statement - Arrhythmogenic right ventricular cardiomyopathy (ARVC) - Dilated cardiomyopathy - Dilated cardiomyopathy and conduction defects

Cardiomyopathies inclusion criteria (Plural) (29339) - Patients with a clear diagnosis and at least one affected relative , OR - Patients with no family history who have a clear diagnosis of primary hypertrophic cardiomyopathy under 40 years of age

Cardiomyopathies exclusion criteria (29339) - Unclear diagnosis or history suggestive of a non-genetic cause

Prior genetic testing guidance (29339) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

PLEASE NOTE: The sensitivity of WGS compared to current diagnostic genetic testing has not yet been established.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 37

It is therefore important that tests which are clinically indicated under local standard practice continue to be carried out.

Arrhythmogenic Right Ventricular Cardiomyopathy prior genetic testing genes (29339) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - ARVC - PKP2 - DSP - DSG2 - DSC2

Closing statement (29339) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 38

Left Ventricular Noncompaction Cardiomyopathy (15044)

Cardiomyopathies eligibility (Left Ventricular Noncompaction Cardiomyopathy and Hypertrophic Cardiomyopathy) (29342)

Level 3 Title Cardiomyopathy (10953)

Level 4 Title Left Ventricular Noncompaction Cardiomyopathy (15044)

Eligibility Relevant diseases: Statement - Left ventricular non-compaction cardiomyopathy - Dilated cardiomyopathy - Hypertrophic cardiomyopathy

Cardiomyopathies inclusion criteria (Plural) (29342) - Patients with a clear diagnosis and at least one affected relative , OR - Patients with no family history who have a clear diagnosis of primary hypertrophic cardiomyopathy under 40 years of age

Cardiomyopathies exclusion criteria (29342) - Unclear diagnosis or history suggestive of a non-genetic cause

Prior genetic testing guidance (29342) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 39

Left Ventricular Noncompaction and Hypertrophic Cardiomyopathy prior genetic testing genes (29342) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - MYBPC3, MYH7, TNNT2 and TNNI3

Closing statement (29342) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 40

Dilated Cardiomyopathy (31340)

Dilated Cardiomyopathy eligibility (31341)

Level 3 Title Cardiomyopathy (10953)

Level 4 Title Dilated Cardiomyopathy (31340)

Eligibility Statement Cardiomyopathies inclusion criteria (Plural) (31341) - Patients with a clear diagnosis and at least one affected relative , OR - Patients with no family history who have a clear diagnosis of primary hypertrophic cardiomyopathy under 40 years of age

Cardiomyopathies exclusion criteria (31341) - Unclear diagnosis or history suggestive of a non-genetic cause

Prior genetic testing guidance (31341) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Dilated Cardiomyopathy prior genetic testing genes (31341) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: ABCC9, ACTC1, CSRP3, LMNA, MYH7, PLN, TNNI3, TNNT2, TPM1, TTN, RBM20

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 41

Closing statement (31341) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 42

Dilated Cardiomyopathy and conduction defects (11027)

Dilated Cardiomyopathy and conduction defects eligibility (29345)

Level 3 Title Cardiomyopathy (10953)

Level 4 Title Dilated Cardiomyopathy and conduction defects (11027)

Eligibility Relevant diseases: Statement - Dilated cardiomyopathy - Dilated cardiomyopathy and conduction defects

Cardiomyopathies inclusion criteria (Plural) (29345) - Patients with a clear diagnosis and at least one affected relative , OR - Patients with no family history who have a clear diagnosis of primary hypertrophic cardiomyopathy under 40 years of age

Cardiomyopathies exclusion criteria (29345) - Unclear diagnosis or history suggestive of a non-genetic cause

Prior genetic testing guidance (29345) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 43

Dilated Cardiomyopathy and conduction defects prior genetic testing genes (29345) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: LMNA

Closing statement (29345) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 44

Hypertrophic Cardiomyopathy (11028)

Cardiomyopathies eligibility (Left Ventricular Noncompaction Cardiomyopathy and Hypertrophic Cardiomyopathy) (29342)

Level 3 Title Cardiomyopathy (10953)

Level 4 Title Hypertrophic Cardiomyopathy (11028)

Eligibility Relevant diseases: Statement - Left ventricular non-compaction cardiomyopathy - Dilated cardiomyopathy - Hypertrophic cardiomyopathy

Cardiomyopathies exclusion criteria (29342) - Unclear diagnosis or history suggestive of a non-genetic cause

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 45

Closing statement (29342) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 46

Congenital heart disease (10954)

Familial congenital heart disease (42212)

Familial congenital heart disease eligibility (42214)

Level 3 Title Congenital heart disease (10954)

Level 4 Title Familial congenital heart disease (42212)

Eligibility Statement Familial congenital heart disease inclusion criteria (42214) Congenital heart disease AND one or more of the following: One or more first degree relative with congenital heart disease, OR Parental consanguinity

Individuals with severe or syndromic disease or with consanguinity and a pedigree in keeping with autosomal recessive inheritance should be recruited according to standard guidance, typically as trios. Disease status of apparently unaffected participants should be determined according to standard clinical practice to detect cryptic disease.

Familial congenital heart disease exclusion criteria (42214) Recognised syndromic presentation (e.g. Noonan syndrome) Likely causative environmental insult during gestation

Prior genetic testing guidance (42214) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 47

Familial congenital heart disease prior genetics testing genes (42214) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: No genes specified

Closing statement (42214) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 48

Syndromic congenital heart disease (42213)

Syndromic congenital heart disease eligibility (42218)

Level 3 Title Congenital heart disease (10954)

Level 4 Title Syndromic congenital heart disease (42213)

Eligibility Statement Syndromic congenital heart disease inclusion criteria (42218) Congenital heart disease, AND One or more malformations outside the cardiovascular system or neurodevelopmental delay

Syndromic congenital heart disease exclusion criteria (42218) Recognised syndromic presentation (e.g. Noonan syndrome) Likely causative environmental insult during gestation

Prior genetic testing guidance (42218) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Syndromic congenital heart disease prior genetic testing genes (42218) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: Microarray genome wide copy number analysis; further testing as dictated by phenotype

Closing statement (42218) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 49

Lymphatic disorders (33334)

Meige disease (34328)

Meige disease eligibility (33445)

Level 3 Title Lymphatic disorders (33334)

Level 4 Title Meige disease (34328)

Eligibility Statement Meige disease inclusion criteria (33445) • Non-congenital lower limb lymphoedema • Multiple affected individuals in the pedigree with family history consistent with autosomal dominant inheritance • Lymphoscintigram (where available) suggestive of deep rerouting with the presence of popliteal nodes

Meige disease exclusion criteria (33445) • Congenital lymphoedema • Lymphoedema of any other segment (e.g. hands/arms/face/genitalia) • Systemic lymphoedema (e.g. intestinal or pulmonary lymphangiectasia, pleural or pericardial effusions) • No family history of lymphoedema • Syndromic lymphoedema including any major structural malformations • Distichiasis (aberrant eyelashes arising from the meibomian glands)

Prior genetic testing guidance (33445) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Meige disease prior genetic testing genes (33445) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: No genes listed

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 50

Closing statement (33445) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 51

Milroy disease (37604)

Milroy disease eligibility (37608)

Level 3 Title Lymphatic disorders (33334)

Level 4 Title Milroy disease (37604)

Eligibility Statement Milroy disease inclusion criteria (37608) • Congenital lower limb lymphoedema, AND • Lymphoscintigram (where available) suggestive of functional aplasia

Milroy disease exclusion criteria (37608) • Non-congenital lymphoedema • Lymphoedema of any other segment (e.g. arms/face) • Syndromic lymphoedema or microcephaly or major structural malformation.

Prior genetic testing guidance (37608) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Milroy disease prior genetic testing genes (37608) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - FLT4

Closing statement (37608) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 52

Lymphoedema distichiasis (37612)

Lymphoedema distichiasis eligibility (37616)

Level 3 Title Lymphatic disorders (33334)

Level 4 Title Lymphoedema distichiasis (37612)

Eligibility Statement Lymphoedema distichiasis inclusion criteria (37616) • Non-congenital lower limb lymphoedema, AND • Distichiasis (extra eyelashes arising from the inner eyelid), AND • Family history (if present) consistent with autosomal dominant inheritance, AND • Lymphoscintigram (where available) suggestive of reflux or rerouting

Lymphoedema distichiasis exclusion criteria (37616) • Congenital lymphoedema • Lymphoedema of any other segment (e.g. arms/face)

Prior genetic testing guidance (37616) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Lymphoedema distichiasis prior genetic testing genes (37616) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: FOXC2

Closing statement (37616) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 53

Ciliopathies (10963)

Congenital malformations caused by ciliopathies (15091)

Bardet-Biedl Syndrome (11046)

Bardet-Biedl Syndrome eligibility (29392)

Level 3 Title Congenital malformations caused by ciliopathies (15091)

Level 4 Title Bardet-Biedl Syndrome (11046)

Eligibility Statement Bardet-Biedl Syndrome inclusion criteria (29392) - unexplained rod-cone dystrophy/ retinal dystrophy OR - at least two of the major diagnostic features associated with Bardet-Biedl syndrome: - Obesity - Polydacyly - Rod-cone dystrophy/ retinal dystrophy/ retinitis pigmentosa - Hypogenitalism - Renal dysplasia

Bardet-Biedl Syndrome exclusion criteria (29392) - non-syndromic retinitis pigmentosa without features suggestive of rod-cone dystrophy/ cone-rod dystrophy - existing molecular confirmation of a diagnosis of Bardet-Biedl syndrome or another ciliopathy

Prior genetic testing guidance (29392) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Bardet-Biedl Syndrome prior genetic testing genes (29392) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice:

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 54

- Genome-wide copy number variation testing (e.g. aCGH, SNP array or other genomic microarray) - ARL6, ALMS1, BBS1, BBS10, BBS12, BBS2, BBS4, BBS5, BBS7, BBS9, MKKS, MKS1 and TTC8

Closing statement (29392) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 55

Joubert syndrome (36478)

Joubert syndrome eligibility (36481)

Level 3 Title Congenital malformations caused by ciliopathies (15091)

Level 4 Title Joubert syndrome (36478)

Eligibility Statement Joubert syndrome inclusion criteria (36481) • A confident clinical diagnosis of Joubert syndrome or Joubert syndrome related disorder based on the presence of the characteristic 'molar tooth sign' in axial MRI images confirmed by a neuroradiologist experienced in the diagnosis of Joubert syndrome. With or without other supportive features of Joubert syndrome. OR • Probable ‘molar tooth sign’ in the presence of additional features of Joubert syndrome: polydactyly, renal cysts, retinal dystrophy, oculomotor apraxia or the characteristic breathing abnormality

Joubert syndrome exclusion criteria (36481) Known genetic cause

Prior genetic testing guidance (36481) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Joubert syndrome prior genetic testing genes (36481) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: • Joubert syndrome gene panel including AHI1, CC2D2A, CEP290, TMEM67

Closing statement (36481) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 56

Rare multisystem ciliopathy disorders (36488)

Rare multisystem ciliopathy disorders eligibility (36491)

Level 3 Title Congenital malformations caused by ciliopathies (15091)

Level 4 Title Rare multisystem ciliopathy disorders (36488)

Eligibility Statement Rare multisystem ciliopathy disorders inclusion criteria (36491) A clinical diagnosis of a rare multisystem ciliopathy including oral-facial-digital syndromes, cranioectodermal dysplasia OR an unclassified rare multisystem ciliopathy based on the presence of two or more core ciliopathy features: two or more core features indicative of a ciliopathy: • polycystic or ‘bright’ kidneys; • cerebellar hypoplasia (especially vermis where visible) / Dandy-Walker malformation or variant; • polydactyly; • short limbs and/or short ribs; • occipital encephalocele • retinal dystrophy This category would be appropriate for fetuses where they meet the above criteria

Rare multisystem ciliopathy disorders exclusion criteria (36491) • A known genetic cause. • A specific diagnosis of Bardet-Biedl syndrome or other ciliopathy with specific recruitment criteria within the 100,000 Genomes project.

Prior genetic testing guidance (36491) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Rare multisystem ciliopathy disorders prior genetic testing genes (36491) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - As dictated by the phenotype including particular consideration of OFD1.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 57

Closing statement (36491) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 58

Respiratory ciliopathies (15092)

Primary ciliary dyskinesia (11047)

Primary ciliary dyskinesia eligibility (29399)

Level 3 Title Respiratory ciliopathies (15092)

Level 4 Title Primary ciliary dyskinesia (11047)

Eligibility Statement Primary ciliary dyskinesia inclusion criteria (29399) - Evidence of chronic sinopulmonary disease as indicated by symptoms and signs including a life-long, wet sounding cough and nasal symptoms, neonatal respiratory distress and chest radiograph with chronic abnormalities. - With or without situs inversus totalis or heterotaxy - With or without infertility - If over 4 years of age nasal Nitric Oxide testing available - With high-speed video analysis showing characteristic disordered ciliary motility, or absent cilia on repeat testing - With transmission electron microscopy results available

Primary ciliary dyskinesia exclusion criteria (29399)

Prior genetic testing guidance (29399) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Primary ciliary dyskinesia prior genetic testing genes (29399) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - DNAH5, DNAH11, CCDC103, CCDC39, CCDC40, DNAI1

Closing statement (29399)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 59

These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 60

Non-CF bronchiectasis (11048)

Non-CF bronchiectasis eligibility (29403)

Level 3 Title Respiratory ciliopathies (15092)

Level 4 Title Non-CF bronchiectasis (11048)

Eligibility Statement Non-CF bronchiectasis inclusion Critieria (29403) • FEV1< 30% predicted and age 4 lobes involved in bronchiectasis < aged 50 OR • Extensive multilobar disease OR • 2 or greater immediate family members affected OR • High chloride in sweat test but CFTR mutation analysis (including extended NHS funded analysis) negative OR • Bronchiectasis with any suspected underlying immunodeficiency aspect to be cross referenced with immunodeficiency GeCiP, e.g. bronchiectasis and recurrent non pulmonary infections OR • Bronchiectasis with any suspected underlying ciliopathy OR • Young’s Syndrome OR • Mounier Kuhn syndrome (tracheobronchomegaly)

Non-CF bronchiectasis exclusion Critieria (29403) Late onset, single lobe disease and those where Asthma or COPD are felt much more clearly the primary driver/ aetiology of the bronchiectasis

Prior genetic testing guidance (29403) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 61

Non-CF bronchiectasis prior genetic testing genes (29403) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - CFTR where clinically indicated

Closing statement (29403) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 62

Dermatological disorders (10956)

Atopy (15084)

Severe multi-system atopic disease with high IgE (15085)

Severe multi-system atopic disease with high IgE eligibility (29367)

Level 3 Title Atopy (15084)

Level 4 Title Severe multi-system atopic disease with high IgE (15085)

Eligibility Statement Severe multi-system atopic disease with high IgE inclusion criteria (29367) - All of the following are required: - Adult patients only - Onset of patients' medical problems is in early childhood (often < 1 year old) - Severe persistent eczema (severe means requiring treatment over and above safe use of potent topical steroids, e.g. topical calcineurin inhibitors, UV light treatment or systemic immunosuppression: azathioprine, cyclosporine A, methotrexate, mycophenolate). Where topical calcineurin inhibitors are used as first line treatment and achieve good symptom control patients should only be included if serum IgE >10000. - Recurrent or chronic S. aureus skin infections, but this criterion may be absent if the patient is receiving systemic immunosuppressive treatment. - Asthma, but the severity can vary from mild to severe - High IgE levels >5000 - Sensitised to a wide variety of aero-allergens and food allergens as measured by ImmunoCAP tests.

Severe multi-system atopic disease with high IgE exclusion criteria (29367) - Those with systemic infections (unlike patients with classical hyper IgE syndrome)

Prior genetic testing guidance (29367) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 63

Closing statement (29367) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 64

Autoimmune skin disorders (33336)

Generalised pustular psoriasis (33646)

Generalised pustular psoriasis eligibility (33450)

Level 3 Title Autoimmune skin disorders (33336)

Level 4 Title Generalised pustular psoriasis (33646)

Eligibility Statement Generalised pustular psoriasis inclusion criteria (33450) • Presence of primary, sterile, macroscopically visible epidermal pustules on non-acral skin • More than one episode of acute pustulation • Diagnosis confirmed by consultant dermatologist

Generalised pustular psoriasis exclusion criteria (33450) • Cases where pustulation is restricted to psoriatic plaques

Prior genetic testing guidance (33450) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Generalised pustular psoriasis prior genetic testing genes (33450) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: No genes listed

Closing statement (33450) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 65

Ectodermal dysplasias (33338)

Ectodermal dysplasia without a known gene mutation (33699)

Ectodermal dysplasia without a known gene mutation eligibility (33457)

Level 3 Title Ectodermal dysplasias (33338)

Level 4 Title Ectodermal dysplasia without a known gene mutation (33699)

Eligibility Statement Ectodermal dysplasia without a known gene mutation inclusion criteria (33457) - Ectodermal dysplasia i.e. abnormality of at least two of the following: - nails - teeth - hair - sweating - With or without additional phenotypic features e.g. clefting, limb defects, hearing loss.

Ectodermal dysplasia without a known gene mutation exclusion criteria (33457) • Mutation in known ectodermal dysplasia gene

Prior genetic testing guidance (33457) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Ectodermal dysplasia without a known gene mutation prior genetic testing genes (33457) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - According to phenotype: EDA, EDAR, EDARADD, WNT10A and/or TP63

Closing statement (33457) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 66

Ichthyoses (33340)

Autosomal recessive congenital ichthyosis (33700)

Autosomal recessive congenital ichthyosis eligibility (33461)

Level 3 Title Ichthyoses (33340)

Level 4 Title Autosomal recessive congenital ichthyosis (33700)

Eligibility Statement Autosomal recessive congenital ichthyosis inclusion criteria (33461) • Neonates, infants, children and adults with a history of generalised red, dry, peeling skin at birth with a mode of inheritance consistent with autosomal recessive transmission • Diagnosis confirmed by consultant dermatologist

Autosomal recessive congenital ichthyosis exclusion criteria (33461) • Ichthyosis vulgaris • STS-related ichthyosis • Syndromic ichthyosis • Keratinopathic ichthyosis • Acquired ichthyosis

Prior genetic testing guidance (33461) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Autosomal recessive congenital ichthyosis prior genetic testing genes (33461) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: TGM1, ALOXE3, ALOX12B, NIPAL4, CYP4F22 and, where appropriate, STS and ABCA12

Closing statement (33461)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 67

These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 68

Keratodermas (33342)

Palmoplantar keratoderma and erythrokeratodermas (33701)

Palmoplantar keratoderma and erythrokeratodermas eligibility (33465)

Level 3 Title Keratodermas (33342)

Level 4 Title Palmoplantar keratoderma and erythrokeratodermas (33701)

Eligibility Statement Palmoplantar keratoderma and erythrokeratodermas inclusion criteria (33465) Diagnosis of one of the following confirmed by consultant dermatologist: • Diffuse palmoplantar keratoderma • Focal keratoderma with or without nail involvement • Pachyonychia congenita phenotype (focal keratoderma with pain and dystrophic nails, oral leukokeratosis and or follicular hyperkeratoses/cysts). • Punctate keratoderma • Striate keratoderma alone • Striate keratoderma with woolly hair • Keratoderma with deafness • Unusual/unique rare keratodermas occuring alone or as part of syndromes. • Erythrokeratoderma

Palmoplantar keratoderma and erythrokeratodermas exclusion criteria (33465)

Prior genetic testing guidance (33465) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Palmoplantar keratoderma and erythrokeratodermas prior genetic testing genes (33465) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - Diffuse palmoplantar keratoderma: KRT9 and KRT1

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 69

- Focal keratoderma: KRT16 and KRT6C - Pachyonychia congenital: KRT6A, KRT6B, KRT6C, KRT16 and KRT17 - Striate keratoderma: KRT1 and KRT16 -Striate keratoderma with woolly hair: cardiac panel including desmosomal genes -Keratoderma with deafness: GJB2

Closing statement (33465) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 70

Familial disseminated superficial actinic porokeratosis (37644)

Familial disseminated superficial actinic porokeratosis eligibility (37750)

Level 3 Title Keratodermas (33342)

Level 4 Title Familial disseminated superficial actinic porokeratosis (37644)

Eligibility Statement Familial disseminated superficial actinic porokeratosis inclusion criteria (37750) • Clinical diagnosis of DSAP, AND • At least 2 affected members over 2 generations, AND • If there is any clinical doubt, skin biopsy confirmation should be sought

Familial disseminated superficial actinic porokeratosis exclusion criteria (37750) • Mibelli, palmoplantar, punctate, sweat duct naevus-related DSAP

Prior genetic testing guidance (37750) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Familial disseminated superficial actinic porokeratosis prior genetic testing genes (37750) No genes listed

Closing statement (37750) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 71

Neurocutaneous disorders (33344)

Undiagnosed neurocutaneous disorders (33686)

Undiagnosed neurocutaneous disorders eligibility (33469)

Level 3 Title Neurocutaneous disorders (33344)

Level 4 Title Undiagnosed neurocutaneous disorders (33686)

Eligibility Statement Undiagnosed neurocutaneous disorders inclusion criteria (33469) All of the following: 1) Abnormal skin pigmentation (café au lait pigmentation, or hypopigmentation, or both) 2) Affected individual has a family history of abnormal skin pigmentation in a first degree relative or is the offspring of a consanguineous relationship 3) Neurological phenotype in at least two of the family members who have skin pigmentary abnormalities (seizures or developmental delay or evidence of congenital abnormality on MRI scan) 4) No diagnosis after assessment by Dermatologist, Neurologist and Geneticist 5) No evidence of chromosomal abnormality on karyotype 6) No pathogenic mutations in the NF1 gene if the child is too young to definitely exclude neurofibromatosis type 1 clinically, and the phenotype could potentially be compatible with that diagnosis

Undiagnosed neurocutaneous disorders exclusion criteria (33469)

Prior genetic testing guidance (33469) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Undiagnosed neurocutaneous disorders prior genetic testing genes (33469) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: NF1 as indicated above

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 72

Closing statement (33469) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 73

Skin adnexa disorders (36587)

Familial cicatricial alopecia (36588)

Familial cicatricial alopecia eligibility (36591)

Level 3 Title Skin adnexa disorders (36587)

Level 4 Title Familial cicatricial alopecia (36588)

Eligibility Statement Familial cicatricial alopecia inclusion criteria (36591) • Cicatricial alopecia diagnosed by a consultant dermatologist • Family history of cicatricial alopecia in at least one first or second degree relative

Familial cicatricial alopecia exclusion criteria (36591)

Prior genetic testing guidance (36591) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Familial cicatricial alopecia prior genetic testing genes (36591) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: No genes listed

Closing statement (36591) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 74

Familial hidradenitis suppurativa (41844)

Familial hidradenitis suppurativa eligibility (41848)

Level 3 Title Skin adnexa disorders (36587)

Level 4 Title Familial hidradenitis suppurativa (41844)

Eligibility Statement Familial hidradenitis suppurativa inclusion criteria (41848) Clinical diagnosis of hidradenitis suppurativa, AND Two or more additional relatives over two generations or more consistent with autosomal dominant inheritance. At least two additional relatives should be available for recruitment.

Disease status of apparently unaffected participants should be determined according to standard clinical practice to detect cryptic disease.

Familial hidradenitis suppurativa exclusion criteria (41848) Acne vulgaris or nodulocystic acne as an isolated clinical feature

Prior genetic testing guidance (41848) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Familial hidradenitis suppurativa prior genetic testing genes (41848) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: No genes specified.

Closing statement (41848)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 75

These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 76

Non-syndromic hypotrichosis (36849)

Non-syndromic hypotrichosis eligibility (36865)

Level 3 Title Skin adnexa disorders (36587)

Level 4 Title Non-syndromic hypotrichosis (36849)

Eligibility Statement Non-syndromic hypotrichosis inclusion criteria (36865) • Generalised (not patchy) scalp hypotrichosis from 6 months of age or earlier with no improvement, AND • Patient older than three years

Non-syndromic hypotrichosis exclusion criteria (36865) • Patchy hypotrichosis • Patchy or episodic regrowth • Syndromic congenital hypotrichosis including ectodermal dysplasias, alopecia with vitamin D resistant rickets, hypotrichosis with dysmorphic facies, hypotrichosis with spondyloepimetaphyseal dysplasia

Prior genetic testing guidance (36865) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Non-syndromic hypotrichosis prior genetic testing genes (36865) No genes listed

Closing statement (36865) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 77

Skin fragility disorders (33346)

Epidermolysis bullosa (33684)

Epidermolysis bullosa eligibility (33473)

Level 3 Title Skin fragility disorders (33346)

Level 4 Title Epidermolysis bullosa (33684)

Eligibility Statement Epidermolysis bullosa inclusion criteria (33473) • Patients with inherited skin fragility and a clinical diagnosis of EB of unknown cause • Diagnosis confirmed by a consultant dermatologist

Epidermolysis bullosa exclusion criteria (33473) • Non-EB genetic causes including porphyria or photosensitivity syndromes • Acquired causes including EB acquisita and bullous drug reactions

Prior genetic testing guidance (33473) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Epidermolysis bullosa prior genetic testing genes (33473) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: KRT5, KRT14, PLEC, DSP, PKP1, JUP, TGM5, EXPH5, ITGA3, ITGA6, ITGB4, DST, COL17A1, LAMA3, LAMA3A, LAMB3, LAMC2, COL7A1

Closing statement (33473) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 78

Peeling skin syndrome (36540)

Peeling skin syndrome eligibility (36543)

Level 3 Title Skin fragility disorders (33346)

Level 4 Title Peeling skin syndrome (36540)

Eligibility Statement Peeling skin syndrome inclusion criteria (36543) • Generalised peeling skin with or without atopy, OR • Acral peeling skin (TGM5 mutations excluded), OR • Peeling skin in association with other features, OR AND • Diagnosis of peeling skin syndrome confirmed by consultant dermatogist

Peeling skin syndrome exclusion criteria (36543) • Peeling skin cases that have not had the genetic testing below

Prior genetic testing guidance (36543) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Peeling skin syndrome prior genetic testing genes (36543) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - For those with acral peeling skin: TGM5

Closing statement (36543) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 79

Sun-exposure related conditions (10958)

Erythropoietic protoporphyria, mild variant (11037)

Erythropoietic protoporphyria, mild variant eligibility (29354)

Level 3 Title Sun-exposure related conditions (10958)

Level 4 Title Erythropoietic protoporphyria, mild variant (11037)

Eligibility Statement Erythropoietic protoporphyria, mild variant inclusion criteria (29354) - History of episodic photosensitivity; - No evidence of an alternative cause of photosensitivity; - Onset of symptoms >60 mins after sun exposure and/or atypical symptoms compared to classical EPP photosensitivity and/or resolution of symptoms <48 hours - Raised red cell free protoporphyrin concentration

Erythropoietic protoporphyria, mild variant exclusion criteria (29354) - Normal red cell protoporphyrin concentration

Prior genetic testing guidance (29354) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Erythropoietic protoporphyria, mild variant prior genetic testing genes (29354) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - FECH

Closing statement (29354) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 80

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 81

Hydroa vacciniforme (15083)

Hydroa Vacciniforme eligibility (29363)

Level 3 Title Sun-exposure related conditions (10958)

Level 4 Title Hydroa vacciniforme (15083)

Eligibility Statement Hydroa Vacciniforme inclusion criteria (29363) - All six of the following: - Photosensitivity - Papulovesicular eruption - Typical varioliform scarring - Significantly elevated Epstein-Barr viral load in the blood - Positive phototest responses to UVA - clinical diagnosis must be made by an experienced photodermatologist able to differentiate this from other photodermatoses clinically

Hydroa Vacciniforme exclusion criteria (29363) - No evidence of Epstein-Barr viral infection

Prior genetic testing guidance (29363) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Closing statement (29363) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 82

Dysmorphic and congenital abnormality syndromes (10959)

Kabuki (28664)

Kabuki syndrome (10960)

Kabuki eligibility (29370)

Level 3 Title Kabuki (28664)

Level 4 Title Kabuki syndrome (10960)

Eligibility Statement Kabuki inclusion criteria (29370) - At least 3 of the typical dysmorphic features: - Arched eyebrows - Sparse lateral one third of the eyebrows - Long palpebral fissures - Everted lower eyelids - Ptosis - Blue sclera - Strabismus - Large dysplastic ears - Flat nasal tip - Broad nasal root - Oligodontia - Abnormal dentition - Full lower lip - Pillowed lower lip - Lip nodules - Lip pits - Micrognathia

- AND at least 1 of the following: - Developmental delay or Intellectual disability - Any of the following malformations - Cleft palate - Congenital Heart Defect - Renal malformation - Ocular malformation - Gastrointestinal malformation

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 83

- Feeding difficulties or Growth retardation - Any of the following neurological problems - Microcephaly - Seizures - Any of the following endocrine/metabolic abnormalities - Early onset prominent breasts/areola - Hypoglycaemia - Growth hormone deficiency - Diabetes insipidus - Unconjugated hyperbillirubinemia

- Any of the following limb and skeletal anomalies

- Persistent fetal pads - Brachydactyly or clinodactyly - Joint dislocation - Joint hypermobility

- Any of the following immunological abnormalities

- Frequent infections - Low Immunoglobulins - Autoimmunity

Kabuki exclusion criteria (29370) - Those with systemic infections (unlike patients with classical hyper IgE syndrome)

Prior genetic testing guidance (29370) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Kabuki prior genetic testing genes (29370) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - KMT2D (MLL2)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 84

Closing statement (29370) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 85

RASopathies (10961)

Noonan syndrome (11039)

RASopathies eligibility (29373)

Level 3 Title RASopathies (10961)

Level 4 Title Noonan syndrome (11039)

Eligibility Relevant diseases: Statement - Noonan syndrome - Noonan syndrome plus other features - Cardio-facio-cutaneous syndrome - LEOPARD syndrome - Costello syndrome - Legius syndrome

RASopathies inclusion (29373) - At least 2 of the suggestive clinical features: - Early feeding difficulty/ failure to thrive - Relative macrocephaly - Short stature - Developmental disability

- At least 1 of: - Cardiomyopathy - Congenital heart disease - Arrhythmia - Suggestive malignancy ( bladder carcinoma, Rhabdomyosarcoma, Leukaemia, phaeochromocytoma) - Skin abnormalities (hyperkeratosis, cafe au lait patches, ulerythema oophorogenes, keratosis pilaris, excess palmar skin)

RASopathies exclusion criteria (29373) - Low birth weight for gestation

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 86

the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

RASopathy Prior Testing Prior Testing Prior Testing Prior Testing Prior Testing prior genetic testing genes (29373) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - PTPN11, RAF1, BRAF, SOS1, KRAS, HRAS, NRAS, SHOC2, CBL, SPRED1, MAP2K1, MAP2K2

Closing statement (29373) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 87

Noonan syndrome plus other features (11040)

RASopathies eligibility (29373)

Level 3 Title RASopathies (10961)

Level 4 Title Noonan syndrome plus other features (11040)

Eligibility Relevant diseases: Statement - Noonan syndrome - Noonan syndrome plus other features - Cardio-facio-cutaneous syndrome - LEOPARD syndrome - Costello syndrome - Legius syndrome

RASopathies inclusion (29373) - At least 2 of the suggestive clinical features: - Early feeding difficulty/ failure to thrive - Relative macrocephaly - Short stature - Developmental disability

RASopathies exclusion criteria (29373) - Low birth weight for gestation

Prior genetic testing guidance (29373) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 88

Closing statement (29373) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 89

Cardio-facio-cutaneous syndrome (11041)

RASopathies eligibility (29373)

Level 3 Title RASopathies (10961)

Level 4 Title Cardio-facio-cutaneous syndrome (11041)

Eligibility Relevant diseases: Statement - Noonan syndrome - Noonan syndrome plus other features - Cardio-facio-cutaneous syndrome - LEOPARD syndrome - Costello syndrome - Legius syndrome

RASopathies inclusion (29373) - At least 2 of the suggestive clinical features: - Early feeding difficulty/ failure to thrive - Relative macrocephaly - Short stature - Developmental disability

RASopathies exclusion criteria (29373) - Low birth weight for gestation

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 90

Closing statement (29373) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 91

LEOPARD syndrome (11042)

RASopathies eligibility (29373)

Level 3 Title RASopathies (10961)

Level 4 Title LEOPARD syndrome (11042)

Eligibility Relevant diseases: Statement - Noonan syndrome - Noonan syndrome plus other features - Cardio-facio-cutaneous syndrome - LEOPARD syndrome - Costello syndrome - Legius syndrome

RASopathies inclusion (29373) - At least 2 of the suggestive clinical features: - Early feeding difficulty/ failure to thrive - Relative macrocephaly - Short stature - Developmental disability

RASopathies exclusion criteria (29373) - Low birth weight for gestation

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 92

Closing statement (29373) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 93

Costello syndrome (11043)

RASopathies eligibility (29373)

Level 3 Title RASopathies (10961)

Level 4 Title Costello syndrome (11043)

Eligibility Relevant diseases: Statement - Noonan syndrome - Noonan syndrome plus other features - Cardio-facio-cutaneous syndrome - LEOPARD syndrome - Costello syndrome - Legius syndrome

RASopathies inclusion (29373) - At least 2 of the suggestive clinical features: - Early feeding difficulty/ failure to thrive - Relative macrocephaly - Short stature - Developmental disability

RASopathies exclusion criteria (29373) - Low birth weight for gestation

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 94

Closing statement (29373) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 95

Legius syndrome (11044)

RASopathies eligibility (29373)

Level 3 Title RASopathies (10961)

Level 4 Title Legius syndrome (11044)

Eligibility Relevant diseases: Statement - Noonan syndrome - Noonan syndrome plus other features - Cardio-facio-cutaneous syndrome - LEOPARD syndrome - Costello syndrome - Legius syndrome

RASopathies inclusion (29373) - At least 2 of the suggestive clinical features: - Early feeding difficulty/ failure to thrive - Relative macrocephaly - Short stature - Developmental disability

RASopathies exclusion criteria (29373) - Low birth weight for gestation

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 96

Closing statement (29373) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 97

Balanced translocations (10962)

Balanced translocations with an unusual phenotype (11045)

Balanced translocations with an unusual phenotype eligibility (29377)

Level 3 Title Balanced translocations (10962)

Level 4 Title Balanced translocations with an unusual phenotype (11045)

Eligibility Statement Balanced translocations with an unusual phenotype inclusion criteria (29377) - De novo translocation where extreme phenotype present - Familial balanced translation that co-segregates with disease - Routine investigations pertaining to the presenting phenotype have been carried out with normal results - Genome-wide copy number variant testing has demonstrated no significant genomic rearrangement at the break points

Balanced translocations with an unusual phenotype exclusion criteria (29377) - Genome-wide copy number variant analysis abnormal and clearly pathogenic

Prior genetic testing guidance (29377) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Balanced translocations with an unusual phenotype prior genetic testing genes (29377) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - Genome-wide copy number variant analysis (e.g. aCGH, SNP array or other genomic microarray)

Closing statement (29377) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 98

Limb disorders (15087)

VACTERL-like phenotypes (10964)

VACTERL-like phenotypes eligibility (29381)

Level 3 Title Limb disorders (15087)

Level 4 Title VACTERL-like phenotypes (10964)

Eligibility Statement VACTERL-like phenotypes inclusion criteria (29381) - At least three out of the five of the following: - Vertebral anomalies - Oesophageal atresia and tracheo-oesophageal fistula - Cardiac malformation - Renal malformation - Limb defect

VACTERL-like phenotypes exclusion criteria (29381) - severe developmental delay - epibulbar dermoid - pre-auricular tags - bilateral limb defect

Prior genetic testing guidance (29381) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

VACTERL-like phenotypes prior genetic testing genes (29381) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - Genome-wide copy number variation testing (e.g. aCGH, SNP array or other genomic microarray) - EFTUD2 (if suggestive clinical findings, e.g. microcephaly, facial asymmetry, inner ear anomalies) - chromosome breakage/Fanconi studies (if suggestive clinical findings, e.g. IUGR, growth retardation,

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 99

microcephaly, hypo/hyperpigmentation)

Closing statement (29381) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 100

DNA repair disorders (10965)

Cockayne syndrome (36497)

Cockayne syndrome eligibility (36500)

Level 3 Title DNA repair disorders (10965)

Level 4 Title Cockayne syndrome (36497)

Eligibility Statement Cockayne syndrome inclusion criteria (36500) • A likely diagnosis of Cockayne syndrome. Major criteria: • Microcephaly (pre- or post-natal onset) • Small stature (pre- or post-natal onset) Minor criteria • Persistently cold peripheries • Bilateral hearing loss (conductive, sensorineural or mixed; not unilateral) • Clinical cutaneous photosensitivity (n.b. skin biopsy testing of DNA repair is NOT REQUIRED) • Tremor • Joint contractures • Progressive loss of body fat • Cataracts • Enophthalmia • Brain imaging abnormality: cerebral calcification, dysmyelination or cerebellar hypoplasia (if more than one present, still count as only ONE minor criterion) A likely diagnosis of Cockayne syndrome is defined as both major criteria and 2 minor criteria.

Cockayne syndrome exclusion criteria (36500) • Known molecular genetic diagnosis

Prior genetic testing guidance (36500) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

PLEASE NOTE: The sensitivity of WGS compared to current diagnostic genetic testing has not yet been established.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 101

It is therefore important that tests which are clinically indicated under local standard practice continue to be carried out.

Cockayne syndrome prior genetic testing genes (36500) Testing as below is strongly recommended PRIOR TO RECRUITMENT as diagnosis of these disorders carries important management implications: - ERCC6 and ERCC8

Closing statement (36500) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 102

Non-Fanconi anaemia (11050)

Non-Fanconi anaemia eligibility (29383)

Level 3 Title DNA repair disorders (10965)

Level 4 Title Non-Fanconi anaemia (11050)

Eligibility Statement Non-Fanconi anaemia inclusion criteria (29383) - Patients referred for Fanconi anaemia chromosome breakage testing, but who are negative for elevated chromosome breakage with mitomycin C/diepoxybutane - Patients with two or more of the following clinical features which overlap with Fanconi: - Skin: hyperpigmentation; Cafe au lait spots; Hypopigmentation - Microsomia: short stature - Upper limbs: Absent/hypoplastic thumbs or radii - Head and face: Microcephaly; micrognathia - Hypogenitalia in males or females - Renal: Ectopic or pelvic; abnormal, horseshoe - Haematology: Unexplained cytopenia

Non-Fanconi anaemia exclusion criteria (29383) - Patients referred for Fanconi anaemia chromosome breakage testing, who are positive for elevated chromosome breakage with mitomycin C/diepoxybutane.

Prior genetic testing guidance (29383) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Non-Fanconi anaemia Gene (29383) - chromosome breakage analysis with mitomycin C/diepoxybutane

Closing statement (29383)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 103

These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 104

Xeroderma Pigmentosum-like disorders (15089)

Xeroderma Pigmentosum-like eligibility (29387)

Level 3 Title DNA repair disorders (10965)

Level 4 Title Xeroderma Pigmentosum-like disorders (15089)

Eligibility Statement Xeroderma Pigmentosum-like inclusion Critiera (29387) - Patients with typical facial lentigines and/or XP-like pattern of photosensitivity - XP has been excluded based on normal unscheduled DNA synthesis and no mutations identified in any of the known XP genes.

Xeroderma Pigmentosum-like exclusion Critiera (29387)

Prior genetic testing guidance (29387) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Xeroderma Pigmentosum-like prior genetic testing genes (29387) No genes listed

Closing statement (29387) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 105

Primary Microcephaly - Microcephalic Dwarfism Spectrum (36505)

Primary Microcephaly - Microcephalic Dwarfism Spectrum eligibility (36508)

Level 3 Title DNA repair disorders (10965)

Level 4 Title Primary Microcephaly - Microcephalic Dwarfism Spectrum (36505)

Eligibility Statement Primary Microcephaly - Microcephalic Dwarfism Spectrum inclusion criteria (36508) • Occipitofrontal circumference (OFC) >2 standard deviations (SD) below mean at birth AND progressive microcephaly to >4SD, OR • OFC >4SD below mean at birth, OR • OFC >3SD below mean at birth AND length >3SD below mean at birth

Primary Microcephaly - Microcephalic Dwarfism Spectrum exclusion criteria (36508) • A known genetic cause. • Dysmorphic physical features or MRI brain indicative of an alternative diagnosis • Evidence of an environmental cause

Prior genetic testing guidance (36508) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Primary Microcephaly - Microcephalic Dwarfism Spectrum prior genetic testing genes (36508) Testing as below is strongly recommended PRIOR TO RECRUITMENT as diagnosis of these disorders carries important management implications: - Array or equivalent genome-wide copy number analysis. - ASPM and other genes dictated by the phenotype

Closing statement (36508) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 106

Autophagy disorders (10966)

Vici Syndrome and other autophagy disorders (11051)

Vici Syndrome and other autophagy disorders eligibility (29390)

Level 3 Title Autophagy disorders (10966)

Level 4 Title Vici Syndrome and other autophagy disorders (11051)

Eligibility Statement Vici Syndrome and other autophagy disorders inclusion criteria (29390) - at least 3 major criteria below OR - at least 1 major criteria and 3 minor criteria below OR - vacuolar myopathy and any other criterion (major or minor)

- Major criteria - Agenesis of the corpus callosum - Cataracts - Cardiomyopathy - Hypopigmentation - Combined immunodeficiency

- Minor criteria - Microcephaly - Sensorineural deafness - Failure to thrive - Myopathy - Neuropathy - Movement disorder

Prior genetic testing guidance (29390) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 107

Vici Syndrome and other autophagy disorders prior genetic testing genes (29390) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - Genome-wide copy number variation testing (e.g. aCGH, SNP array or other genomic microarray)

Closing statement (29390) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 108

Dysmorphic disorders (36595)

Coarse facial features including Coffin-Siris-like disorders (36596)

Coarse facial features including Coffin-Siris-like disorders eligibility (36599)

Level 3 Title Dysmorphic disorders (36595)

Level 4 Title Coarse facial features including Coffin-Siris-like disorders (36596)

Eligibility Statement Coarse facial features including Coffin-Siris-like disorders inclusion criteria (36599) • Coarse facial features warranting further investigation -particularly those with other medical problems, additional dysmorphic facial features or intellectual disability, AND • Previous investigations to exclude metabolic disorder including a minimum of plasma amino acids, urine organic acids and urine GAGs, AND

Coarse facial features including Coffin-Siris-like disorders exclusion criteria (36599) • Known genetic aetiology • Untreated congenital hypothyroidism • Metabolic investigations indicative of likely inborn error of metabolism (these individuals should follow a metabolic pathway of investigation and recruitment) • Clinical features of an insulin resistance / lipodystrophy disorder, RASopathy or overgrowth disorder (these individuals should be investigated and recruited to the relevant specific rare disorder)

Prior genetic testing guidance (36599) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Coarse facial features including Coffin-Siris-like disorders prior genetic testing genes (36599) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - Guided by phenotype. There should be a low threshold for Ras-MAPK gene testing, and 11p15 methylation analysis should be considered

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 109

- If clinical diagnosis of Pallister-Killian syndrome is considered likely, a skin biopsy for chromosome analysis should be performed prior to recruitment

Closing statement (36599) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 110

Familial non-syndromic cleft lip and or familial cleft palate (37565)

Familial Non-syndromic cleft lip and or familial cleft palate eligibility (37569)

Level 3 Title Dysmorphic disorders (36595)

Level 4 Title Familial non-syndromic cleft lip and or familial cleft palate (37565)

Eligibility Statement Familial Non-syndromic cleft lip and or familial cleft palate inclusion criteria (37569) • Familial cleft lip with or without cleft palate, or cleft palate alone AND • At least 4 affected family members over at least 3 generations, OR • At least 3 affected siblings with no additional family history AND • At least 3 affected individuals available to participate in the study

Familial Non-syndromic cleft lip and or familial cleft palate exclusion criteria (37569) • Van der Woude syndrome or Stickler syndrome clinically diagnosed • Syndromic clefting disorders (see syndromic clefting disorders eligibility criteria)

Prior genetic testing guidance (37569) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Familial Non-syndromic cleft lip and or familial cleft palate prior genetic testing genes (37569) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - aCGH or equivalent - IRF6 if lip pits in any member or cleft lip AND palate present in the family

Closing statement (37569) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 111

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 112

Syndromic cleft lip and or cleft palate (37573)

Syndromic cleft lip and or cleft palate eligibility (37741)

Level 3 Title Dysmorphic disorders (36595)

Level 4 Title Syndromic cleft lip and or cleft palate (37573)

Eligibility Statement Syndromic cleft lip and or cleft palate inclusion criteria (37741) • Cleft palate and/or cleft lip palate AND • At least one additional structural malformation, OR • Height/length or head circumference >3SDs from the mean, OR • Dysmorphism, OR • Intellectual disability – moderate or more severe, OR • Autism spectrum disorder

Syndromic cleft lip and or cleft palate exclusion criteria (37741) • Known teratogenic or genetic cause

Prior genetic testing guidance (37741) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Syndromic cleft lip and or cleft palate prior genetic testing genes (37741) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - aCGH or equivalent - IRF6 if suspected Van der Woude syndrome; COL2A1, COL11A1 and COL11A2 in suspected Stickler syndrome (as guided by ocular phenotype)

Closing statement (37741)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 113

These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 114

PHACE(S) syndrome (37578)

PHACE(S) syndrome eligibility (37582)

Level 3 Title Dysmorphic disorders (36595)

Level 4 Title PHACE(S) syndrome (37578)

Eligibility Statement PHACE(S) syndrome inclusion criteria (37582) • Haemangioma on the scalp or face of >5cm, AND at least 1 major or 2 minor criteria: • MAJOR: Anomaly of major cerebral arteries; Posterior fossa anomaly; Aortic arch anomaly; Ocular posterior segment anomaly; sternal defect • MINOR: Persistent embryonic artery other than trigeminal artery; Enhancing extra-axial lesion with features consistent with intracranial haemangioma or midline anomaly or neuronal migration defect; Ventricular septal defect or right aortic arch; Ocular anterior segment anomaly; Hypopituitarism/ectopic thyroid

PHACE(S) syndrome exclusion criteria (37582) • Clinical features suggestive of Sturge-Weber syndrome

Prior genetic testing guidance (37582) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

PHACE(S) syndrome prior genetic testing genes (37582) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - aCGH or equivalent

Closing statement (37582) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 115

Radial dysplasia (37636)

Radial dysplasia eligibility (37640)

Level 3 Title Dysmorphic disorders (36595)

Level 4 Title Radial dysplasia (37636)

Eligibility Statement Radial dysplasia inclusion criteria (37640) • Bilateral radial dysplasia, OR • Unilateral radial dysplasia with positive family history, parental consanguinity or additional syndromic features (such as at least one additional structural malformation, height/length or head circumference >3SDs from the mean, dysmorphism, moderate or worse intellectual disability or autism spectrum disorder)

Radial dysplasia exclusion criteria (37640) • Known genetic cause • Known teratogenic cause

Prior genetic testing guidance (37640) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Radial dysplasia prior genetic testing genes (37640) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - aCGH or equivalent - Fanconi breakage testing (if features suggestive of Fanconi anaemia) - TBX5 (if phenotype suggestive of Holt-Oram syndrome) - RBM8A (if aCGH or clinical features suggestive of TAR syndrome)

Closing statement (37640) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 116

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 117

Fetal disorders (38586)

Fetal hydrops (37586)

Fetal hydrops eligibility (37590)

Level 3 Title Fetal disorders (38586)

Level 4 Title Fetal hydrops (37586)

Eligibility Statement Fetal hydrops inclusion criteria (37590) • Non-immune fetal hydrops surviving >16 weeks gestation, AND • Normal infection screen (including parvovirus, CMB, rubella +- syphilis, VZV), AND • No evidence of Rh or other blood group incompatibility, AND • Haemoglobinopathy excluded where present in parent, AND • Normal fetal +- neonatal amniotic fluid screen for storage disorders (glycosaminglycans), AND • If IUGR: normal placental artery dopplers AND middle cerebral artery Doppler <1.5MoM

Please note: samples from ongoing pregnancies should NOT be included

Fetal hydrops exclusion criteria (37590) • Isolated structural cardiac anomaly or cardiac arrhythmia • Fetal tumour • Fetal lung mass • Maternal pre-eclampsia • Poorly controlled maternal DM/hypothyroidism • Twin-twin transfusion

Prior genetic testing guidance (37590) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Fetal hydrops prior genetic testing genes (37590)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 118

Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - Consideration of RASopathy screen (low threshold for PTPN11 exons 3 & 8) - Low threshold Niemann Pick analysis if splenomegaly or Ashkenazi ancestry

Closing statement (37590) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 119

Unexplained monogenic fetal disorders (38665)

Unexplained monogenic fetal disorders eligibility (38668)

Level 3 Title Fetal disorders (38586)

Level 4 Title Unexplained monogenic fetal disorders (38665)

Eligibility Statement Unexplained monogenic fetal disorders inclusion criteria (38668) Fetuses with a normal chromosome test considered likely to have a monogenic disease by a clinician expert in fetal genetics

Please note: samples from ongoing pregnancies should NOT be included

Unexplained monogenic fetal disorders exclusion criteria (38668) • Likely teratogenic, infectious or chromosomal cause • Likely placental cause

Prior genetic testing guidance (38668) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Unexplained monogenic fetal disorders prior genetic testing genes (38668) Where rapid aneuploidy testing and/or detailed chromosome testing (e.g. microarray) is indicated, this should be completed PRIOR TO RECRUITMENT. Further genetic testing in line with current local practice should be considered in parallel with recruitment but is NOT required prior to recruitment.

Closing statement (38668) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 120

Endocrine disorders (10967)

Adrenal disorders (10969)

Congenital adrenal hypoplasia (11053)

Congenital adrenal hypoplasia eligibility (29408)

Level 3 Title Adrenal disorders (10969)

Level 4 Title Congenital adrenal hypoplasia (11053)

Eligibility Statement Congenital adrenal hypoplasia inclusion criteria (29408) - Combined primary glucocorticoid and mineralocorticoid insufficiency OR - Isolated primary glucocorticoid insufficiency OR - Isolated primary mineralocorticoid insufficiency

Congenital adrenal hypoplasia exclusion criteria (29408) - Congenital adrenal hyperplasia - Autoimmune Addison disease - Secondary adrenal insufficiency - Iatrogenic adrenal suppression due to glucocorticoid use - Post-infective adrenal dysfunction/haemorrhage/infiltrative disease - Metabolic adrenal insufficiency (X-linked adrenoleukodystrophy, mitochondrial disorders, Wolman syndrome) - Confirmed diagnosis of salt loss (e.g. pseudohypoaldosteronism type I or II, UTI, urethral values, renal conditions, cerebral salt loss etc.)

Prior genetic testing guidance (29408) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Congenital adrenal hypoplasia prior genetic testing genes (29408)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 121

Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - NR0B1 for boys with combined glucocorticoid and mineralocorticoid insufficiency with a family history consistent with an X-linked disorder

Closing statement (29408) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 122

Disorders of calcium homeostasis (10970)

Familial or syndromic hypoparathyroidism (11054)

Familial or syndromic hypoparathyroidism eligibility (29412)

Level 3 Title Disorders of calcium homeostasis (10970)

Level 4 Title Familial or syndromic hypoparathyroidism (11054)

Eligibility Statement Familial or syndromic hypoparathyroidism inclusion criteria (29412) - Hypocalcaemia, congenital or acquired - High normal or raised serum phosphate - Low or low-normal plasma parathyroid hormone in the presence of hypocalcaemia - Normal serum 25-OH vitamin D - Low serum magnesium may be present, but is not required for diagnosis AND - At least one first degree relative with hypoparathyroidism, OR - At least one additional congenital anomaly or unexplained medical disorder likely to be causally related to the hypoparathyroidism

Familial or syndromic hypoparathyroidism exclusion criteria (29412) - Significant renal failure (estimated creatinine clearance < 30 mls/min), renal dysplasia, sensorineural deafness (HDR syndrome). - Skeletal manifestations of pseudohypoparathyroidism. - Elevated parathyroid hormone.

Prior genetic testing guidance (29412) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Familial or syndromic hypoparathyroidism prior genetic testing genes (29412) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 123

practice: - CASR

Closing statement (29412) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 124

Gonadal and sex development disorders (36923)

Disorders of sex development (36852)

Disorders of sex development eligibility (36879)

Level 3 Title Gonadal and sex development disorders (36923)

Level 4 Title Disorders of sex development (36852)

Eligibility Statement Disorders of sex development inclusion criteria (36879) 46,XX disorder of sex development • Normal 46,XX karyotype following microarray testing, AND • Absence of SRY, AND • At least one of (a) genital ambiguity, (b) absence or anomaly of the Mullerian structures, or (c) gonadal dysgenesis

46,XY disorder of sex development • Normal 46,XY karyotype following microarray testing, AND • Presence of SRY, AND • At least one of (a) ambiguity of the external genitalia, (b) presence of Mullerian structures, or (c) gonadal dysgenesis

Disorders of sex development exclusion criteria (36879) 46,XX disorder of sex development • Antenatal history suggestive of non-genetic cause, e.g. maternal androgen exposure • Biochemical or genetic evidence of 21-hydroxylase deficiency, 11-hydroxylase deficiency, 3 beta hydroxysteroid dehydrogenase deficiency type 2, cytochrome P450 reductase (POR) related disorders and 17 alpha hydroxylase deficiency.

46,XY disorder of sex development • Isolated hypospadias • Biochemical or genetic evidence of 5 alpha reductase deficiency, 3 beta hydroxysteroid dehydrogenase deficiency type 2, cytochrome P450 reductase (POR) related disorders, aromatase deficiency and androgen insensitivity syndrome.

Prior genetic testing guidance (36879) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 125

the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Disorders of sex development prior genetic testing genes (36879) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice:

46,XX disorder of sex development • In situ study to exclude presence of SRY • Exclusion of CNV associated with 46 XX DSD • CYP21A2 and CYP11B1 if indicated by steroid biochemistry - steroid biochemistry to assess whether these disorders needed genetic testing would be a requirement before inclusion.

46,XY disorder of sex development • In situ study to prove presence of SRY • Exclusion of CNV associated with 46 XY DSD • Obligatory endocrinological assessment and steroid biochemistry (including testosterone, DHT) and where indicated from biochemical investigations analysis of HSD17B3, SRD5A2 and Androgen receptor)

Closing statement (36879) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 126

Early onset familial premature ovarian insufficiency (36851)

Early onset familial premature ovarian insufficiency eligibility (36874)

Level 3 Title Gonadal and sex development disorders (36923)

Level 4 Title Early onset familial premature ovarian insufficiency (36851)

Eligibility Statement Early onset familial premature ovarian insufficiency inclusion criteria (36874) • 4 consecutive months of amenorrhoea (primary or secondary), AND • Elevated serum FSH of >30IU/L on two separate occasions at least 6 weeks apart, AND • Age of onset is <30 years, AND • At least one other close family member (sister, mother, aunt or first cousin) with POF, AND • Availability of at least 1 additional affected family member to take part in the project

No male relatives should be recruited to this disorder. Unaffected female relatives should only be recruited if they are aged over 45 years, AND menstruation ceased after the age of 45 years.

Early onset familial premature ovarian insufficiency exclusion criteria (36874) • X chromosome abnormality such as Turner syndrome • Presence of FMR1 premutation • Iatrogenic cause (bilateral oophorectomy, chemotherapy, radiotherapy or any other iatrogenic cause) • Presence of thyroid or adrenal auto-antibodies

Prior genetic testing guidance (36874) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Early onset familial premature ovarian insufficiency prior genetic testing genes (36874) Testing for fragile X premutation and chromosome abnormalities is strongly recommended PRIOR TO RECRUITMENT as these may not be reliably detected by WGS using current analysis techniques.

Closing statement (36874)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 127

These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 128

Growth hormone disorders (10971)

IUGR and IGF abnormalities (11057)

IUGR eligibility (29416)

Level 3 Title Growth hormone disorders (10971)

Level 4 Title IUGR and IGF abnormalities (11057)

Eligibility Statement IUGR inclusion criteria (29416) - Height Standard Deviation Score (SDS) <-3 (very significant short stature - well below the 0.4th centile) AND - At least one of: - being born small for gestational (birth weight and/or length <-2SDS), ± a history of intra-uterine growth restriction - Body disproportion - e.g. discrepancy between stature and head size, limb to spine disproportion, limb asymmetry - Dysmorphic features e.g. facial dysmorphism, polydactyly/syndactyly, ear abnormalities - Aberration in the GH-IGF axis (evidence of GH insensitivity or deficiency) - Other pituitary hormonal deficiencies - Family history (short stature that is explained or idiopathic in parents, affected siblings,cousins) and/or consanguinity - Other features such as cleft palate, hearing loss, visual impairment with eye abnormalities including anophthalmia/microphthalmia, optic nerve hypoplasia, retinal dystrophy, forebrain abnormalities and learning difficulties - For all patients with no abnormalities of the GH-IGF-I axis classified as Idiopathic Short Stature or who are small for gestational age with failure of catch up growth, a skeletal survey should be performed.

IUGR exclusion criteria (29416) - Acquired causes of short stature, e.g. autoimmune, intracranial neoplasia, infective causes such as Group B Streptococcal meningitis, Langerhans cell Histiocytosis, trauma, previous treatment for malignancy including irradiation, exogenous glucocorticoid use, psychosocial growth failure, chronic disease - Syndromes associated with short stature such as Turner syndrome, Noonan syndrome, Down syndrome, other chromosomal disorders. However, if the patient has a clinical diagnosis of, e.g. Noonan syndrome, and testing of known genes associated with the syndrome has not identified a pathogenic mutation, then they should be included in the 100000 genomes study. - Foetal alcohol syndrome - Genetically proven skeletal dysplasias such as hypochondroplasia or achondroplasia - Genetically proven Silver-Russell syndrome

Prior genetic testing guidance (29416)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 129

- Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

IUGR prior genetic testing genes (29416) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - All patients with short stature and other features such as developmental delay and dysmorphism should have a DNA microarray with no pathogenic copy number variants detected prior to enrolment - Additional genetic testing should have been performed as appropriate

Closing statement (29416) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 130

Hypothalamic and pituitary disorders (42204)

Idiopathic hypogonadotropic hypogonadism (41827)

Idiopathic hypogonadotropic hypogonadism eligibility (41832)

Level 3 Title Hypothalamic and pituitary disorders (42204)

Level 4 Title Idiopathic hypogonadotropic hypogonadism (41827)

Eligibility Statement Idiopathic hypogonadotropic hypogonadism inclusion criteria (41832) Delayed or absent puberty with low or suppressed gonadotropins (including primary amenorrhoea, oligo/azoospermia with low testosterone. Bilateral cryptorchidism with micophallus is suggestive of congenital IHH) AND at least one of the following, Parental consanguinity, OR One or more similarly affected first, second or third degree relative, OR Syndromic features such as anosmia, cleft lip or palate, deafness, renal agenesis, neurological disorders

Idiopathic hypogonadotropic hypogonadism exclusion criteria (41832) Acquired structural hypothalamo-pituitary disease History of anabolic steroid use, recent history of glucocorticoid or opiate use Severe intercurrent illness, anorexia, or other forms of undernourishment Evidence of primary hypogonadism Co-existent pituitary hormone deficiency Features of Bardet Biedl, CHARGE syndromes, or other complex syndromes for which UKGTN testing exists

Prior genetic testing guidance (41832) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 131

Idiopathic hypogonadotropic hypogonadism prior genetic testing genes (41832) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: No genes specified

Closing statement (41832) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 132

Obesity syndromes (10973)

Significant early-onset obesity with or without other endocrine features and short stature (11060)

Obesity eligibility (29426)

Level 3 Title Obesity syndromes (10973)

Level 4 Title Significant early-onset obesity with or without other endocrine features and short stature (11060)

Eligibility Statement Obesity inclusion criteria (29426) - Syndromic or non-syndromic severe obesity (BMI > 3SD above the mean) - Onset before age 5 years

Obesity exclusion criteria (29426) - Known cause of obesity, e.g. steroid treatment

Prior genetic testing guidance (29426) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Obesity prior genetic testing genes (29426) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - Genome-wide copy number variation testing (e.g. aCGH, SNP array or other genomic microarray) - Where the phenotype is recognisable and is caused by 1-2 principle genes, these should have been tested prior to recruitment

Closing statement (29426) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 133

Rare subtypes of diabetes (15099)

Familial young-onset non-insulin-dependent diabetes (15103)

Diabetes eligibility (29420)

Level 3 Title Rare subtypes of diabetes (15099)

Level 4 Title Familial young-onset non-insulin-dependent diabetes (15103)

Eligibility Statement Diabetes inclusion criteria (29420) - Diagnosis of diabetes <30 years of age - Not insulin dependent (>=1 years without insulin treatment) - Non-obese (BMI <30)

Unaffected family members should only be recruited if they have had testing to rule out diabetes (e.g. normal HbA1c) at or over the age of 40.

Diabetes exclusion criteria (29420) - One or more autoantibodies positive

Prior genetic testing guidance (29420) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Familial young-onset non-insulin-dependent diabetes prior genetic testing genes (29420) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: No genes listed

Closing statement (29420)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 134

These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 135

Hyperinsulinism (15105)

Hyperinsulinism eligibility (29423)

Level 3 Title Rare subtypes of diabetes (15099)

Level 4 Title Hyperinsulinism (15105)

Eligibility Statement Hyperinsulinism inclusion criteria (29423) - Hypoglycaemia onset before 12 years of age - Drug-treated for >=3 months or pancreatectomy - Intravenous glucose infusion rate required to maintain normoglycaemia >8mg/kg/min - Detectable serum insulin or C-Peptide when blood glucose is less than 3mmol/L

Hyperinsulinism exclusion criteria (29423) - Hypoglycaemia in the neonatal period which resolved without treatment - Hypoglycaemia in the context of systemic neonatal disease e.g. sepsis

Prior genetic testing guidance (29423) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Closing statement (29423) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 136

Neonatal diabetes (diagnosed less than 6 months) (30553)

Neonatal diabetes eligibility (30555)

Level 3 Title Rare subtypes of diabetes (15099)

Level 4 Title Neonatal diabetes (diagnosed less than 6 months) (30553)

Eligibility Statement Neonatal diabetes inclusion criteria (30555) - Neonatal diabetes diagnosed < 6 months NOTE: diabetes diagnosed before 6 months of age almost universally has a monogenic aetiology. Families should be recruited if diabetes is diagnosed according to WHO criteria before the age of 6 months, and the diagnostic panel of known genes is negative.

Neonatal diabetes exclusion criteria (30555) - One or more pancreatic autoantibodies (GAD, IA2, ICA) positive (titre >99th population centile)

Prior genetic testing guidance (30555) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Neonatal diabetes prior genetic testing genes (30555) Testing as below is strongly recommended PRIOR TO RECRUITMENT as WGS will not detect treatable mutations quickly enough to prevent irreversible neurological damage in a subset of patients: Neonatal diabetes screen which is offered at the Exeter Molecular Genetics Laboratory or an equivalent genetic test.

Closing statement (30555) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 137

Diabetes with additional phenotypes suggestive of a monogenic aetiology (30559)

Insulin resistance (including lipodystrophy) (30561)

Insulin resistance eligibility (30562)

Level 3 Title Rare subtypes of diabetes (15099)

Level 4 Title Insulin resistance (including lipodystrophy) (30561)

Eligibility Statement Insulin resistance inclusion criteria (30562) - Diagnosis of diabetes <25 years AND - Not insulin dependent (>=3 years without insulin treatment) AND - Non-obese (BMI <30) AND - Acanthosis nigricans AND - Biochemical confirmation of severe insulin resistance.

Insulin resistance exclusion criteria (30562) - One or more pancreatic autoantibodies (GAD, IA2, ICA) positive (titre >99th population centile)

Prior genetic testing guidance (30562) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Closing statement (30562) These requirements will be kept under continual review during the main programme and may be subject to change.

Insulin resistant prior genetic testing genes (30562) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - LMNA if partial lipodystrophy phenotype

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 138

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 139

Multi-organ autoimmune diabetes (30563)

Autoimmune diabetes eligibility (30564)

Level 3 Title Rare subtypes of diabetes (15099)

Level 4 Title Multi-organ autoimmune diabetes (30563)

Eligibility Statement Autoimmune diabetes inclusion criteria (30564) - Diabetes AND - >=2 autoimmune disorders with >=2 of these diagnosed <10 years.

Autoimmune diabetes exclusion criteria (30564)

Prior genetic testing guidance (30564) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Autoimmune Diabetes prior genetic testing genes (30564) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - AIRE if Addison’s disease is present

Closing statement (30564) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 140

Thyroid disorders (42208)

Congenital hypothyroidism (41908)

Congenital hypothyroidism eligibility (41912)

Level 3 Title Thyroid disorders (42208)

Level 4 Title Congenital hypothyroidism (41908)

Eligibility Statement Congenital hypothyroidism inclusion criteria (41912) Congenital Hypothyroidism defined biochemically as: Primary CH: neonatal or early onset elevated TSH with subnormal or normal thyroid hormone levels Central CH: neonatal or early onset subnormal thyroid hormone levels with normal or subnormal TSH

Preferred inclusion criteria – cases from multicase families or consanguineous backgrounds or (in primary CH) with additional extra-thyroidal features.

Congenital hypothyroidism exclusion criteria (41912) A high likelihood that the phenotype is completely explained by an acquired aetiology (eg autoimmunity, maternal autoantibodies, iodine deficiency) A pathogenic mutation in a known causative gene which completely explains the phenotype.

Prior genetic testing guidance (41912) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Congenital hypothyroidism prior genetic testing genes (41912) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: Consideration of FOXE1, GNAS, SLC26A4, TSHR, TPO, DUOX2, TG

Closing statement (41912)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 141

These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 142

Resistance to thyroid hormone (41916)

Resistance to thyroid hormone eligibility (41920)

Level 3 Title Thyroid disorders (42208)

Level 4 Title Resistance to thyroid hormone (41916)

Eligibility Statement Resistance to thyroid hormone inclusion criteria (41920) Resistance to thyroid hormone defined biochemically as elevated levels of T3 and/or T4 with non-suppressed TSH levels

Resistance to thyroid hormone exclusion criteria (41920) A high likelihood that the phenotype is completely explained by an acquired aetiology (eg drugs, assay interference, iodine deficiency, TSH-secreting pituitary tumour). A pathogenic mutation in a known causative gene which completely explains the phenotype.

Prior genetic testing guidance (41920) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Resistance to thyroid hormone prior genetic testing genes (41920) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: Elevated T3, low/normal T4 and/or clinical features suggestive of Allan-Herndon-Dudley syndrome: SLC16A2 (MCT8) Elevated T3, low/normal T4, and/or clinical features suggestive of RTHalpha: THRA Raised T4, normal/low T3, high reverse T3, low plasma selenium: SECISBP2, TRNAU1

Closing statement (41920) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 143

Gastroenterological disorders (38581)

Gastrointestinal disorders (38582)

Infantile enterocolitis and monogenic inflammatory bowel disease (37490)

Infantile enterocolitis and monogenic inflammatory bowel disease eligibility (37498)

Level 3 Title Gastrointestinal disorders (38582)

Level 4 Title Infantile enterocolitis and monogenic inflammatory bowel disease (37490)

Eligibility Statement Infantile enterocolitis and monogenic inflammatory bowel disease inclusion criteria (37498) - Chronic inflammatory bowel disease and inflammatory bowel disease like intestinal inflammation - Age of onset intestinal inflammation less than complete 2 years of age. - Histology confirmed intestinal inflammation with first endoscopy (less than 2.5 years of age).

Infantile enterocolitis and monogenic inflammatory bowel disease exclusion criteria (37498) - Acute infectious gastroenteritis/enterocolitis due to common pathogens (Rotavirus, Norovirus, Salmonella etc.)

Prior genetic testing guidance (37498) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Infantile enterocolitis and monogenic inflammatory bowel disease prior genetic testing genes (37498) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice:

- In case of enterocolitis less than 3 month of age IL10, IL10RA and IL10RB signalling defects should be excluded. - In case of enterocolitis with infantile diabetes and autoimmunity IPEX (FOXP3) should be excluded.

Closing statement (37498)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 144

These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 145

Gastrointestinal epithelial barrier disorders (37772)

Gastrointestinal epithelial barrier disorders eligibility (40230)

Level 3 Title Gastrointestinal disorders (38582)

Level 4 Title Gastrointestinal epithelial barrier disorders (37772)

Eligibility NB. Clinical test guidance: Statement General biopsy refers to biopsy of abnormal intestinal features Inflammatory markers refers to C reactive protein General Imaging Diagnostics refers to Endoscopy

Gastrointestinal epithelial barrier disorders inclusion criteria (40230) • Proven histological evidence of epithelial disorder on gut biopsy: Epithelial dysmorphology characterised by e.g. epithelial detachment abnormal epithelial cell polarisation, epithelial cell crowding/tufting and increased apoptotic activity of the epithelial layer.

Gastrointestinal epithelial barrier disorders exclusion criteria (40230) • Evidence of primary immune deficiency. • Histopathology in keeping with conventional GI disorders such as IBD without features described above.

Prior genetic testing guidance (40230) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Gastrointestinal epithelial barrier disorders prior genetic testing genes (40230) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: • EPCAM, MYO5B, ADAM17, IKBKG

Closing statement (40230) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 146

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 147

Non-syndromic familial congenital anorectal malformations (41868)

Non-syndromic familial congenital anorectal malformations eligibility (41872)

Level 3 Title Gastrointestinal disorders (38582)

Level 4 Title Non-syndromic familial congenital anorectal malformations (41868)

Eligibility Statement Non-syndromic familial congenital anorectal malformations inclusion criteria (41872) Congenital anorectal malformation regardless of phenotype severity (imperforate anus through to cloaca) AND At least one first or second degree relative with an anorectal malformation.

Disease status of apparently unaffected participants should be determined according to standard clinical practice to detect cryptic disease.

Unaffected individuals should not be recruited. Recruitment in such families should favour multiplex families over single isolated cases. These singleton recruits will not contribute to the overall singleton monitoring metrics applied to GMCs.

Non-syndromic familial congenital anorectal malformations exclusion criteria (41872) Additional clinical features suggestive of a multisystem syndrome other than VACTERL association. For example, please do not recruit cases with clinical diagnoses of Currarino syndrome, Townes-Brockes syndrome or Pallister-Hall syndrome.

Prior genetic testing guidance (41872) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Non-syndromic familial congenital anorectal malformations prior genetic testing genes (41872) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: No genes specified

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 148

Closing statement (41872) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 149

Early onset or familial intestinal pseudo obstruction (41876)

Early onset or familial intestinal pseudo obstruction eligibility (41880)

Level 3 Title Gastrointestinal disorders (38582)

Level 4 Title Early onset or familial intestinal pseudo obstruction (41876)

Eligibility Statement Early onset or familial intestinal pseudo obstruction inclusion criteria (41880) A. Chronic visceral dilatation including part or all of the small intestine (chronic intestinal pseudo-obstruction)

AND one of:

B1. Diagnosis within first year of life (majority will have symptoms from the neonatal period) B2. Diagnosis at any age but with at least one first or second degree relative with a diagnosis of either IPO or another severe digestive motility disorder (enteric dysmotility; oesophageal achalasia, megacolon, megarectum).

Early onset or familial intestinal pseudo obstruction exclusion criteria (41880) Proven mitochondrial myopathy (MNGIE) [by MRI / muscle biopsy in suspected cases] Proven early onset secondary cause e.g. muscular dystrophy or cystic fibrosis [with relevant testing if clinical suspicion]

Prior genetic testing guidance (41880) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 150

Early onset or familial intestinal pseudo obstruction prior genetic testing genes (41880) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: No genes specified

Closing statement (41880) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 151

Growth disorders (10974)

Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders (10975)

Classical Beckwith-Wiedemann syndrome (11063)

Beckwith-Wiedemann syndrome eligibility criteria (29430)

Level 3 Title Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders (10975)

Level 4 Title Classical Beckwith-Wiedemann syndrome (11063)

Eligibility Relevant diseases: Statement - Classical Beckwith-Wiedemann syndrome - Atypical Beckwith-Wiedemann syndrome

Beckwith-Wiedemann syndrome inclusion criteria (29430) A. Clinical diagnosis of BWS meeting standard clinical diagnostic criteria AND • no detectable cause, OR • balanced chromosomal aberration (translocation/inversion), OR • multilocus methylation defect consistent with an in trans imprinting defect, OR • Isolated/single locus 11p15 methylation defect with is a family history of Beckwith-Wiedemann syndrome

Recruitment in these families should follow standard guidance.

B. Clinical diagnosis of BWS meeting standard clinical diagnostic criteria AND • Isolated/single locus 11p15 methylation defect (for example KvDMR loss of methylation or H19 hypermethylation) without a family history of Beckwith-Wiedemann syndrome.

Recruitment to families in group B should only occur as proband-mother-father trios.

Beckwith-Wiedemann syndrome exclusion criteria (29430) Beckwith-Wiedemann syndrome exclusion criteria (29430) • Paternal uniparental disomy (UPD) 11p15 • CDKN1C mutation

Prior genetic testing guidance (29430)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 152

Beckwith-Wiedemann syndrome prior genetic testing genes (29430) 11p15 methylation testing is required PRIOR TO RECRUITMENT as molecular diagnosis determines eligibility and surveillance, and methylation abnormalities cannot be detected on WGS.

- Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice:

CDKN1C

Closing statement (29430) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 153

Atypical Beckwith-Wiedemann syndrome (11064)

Beckwith-Wiedemann syndrome eligibility criteria (29430)

Level 3 Title Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders (10975)

Level 4 Title Atypical Beckwith-Wiedemann syndrome (11064)

Eligibility Relevant diseases: Statement - Classical Beckwith-Wiedemann syndrome - Atypical Beckwith-Wiedemann syndrome

Recruitment in these families should follow standard guidance.

Recruitment to families in group B should only occur as proband-mother-father trios.

Beckwith-Wiedemann syndrome exclusion criteria (29430) Beckwith-Wiedemann syndrome exclusion criteria (29430) • Paternal uniparental disomy (UPD) 11p15 • CDKN1C mutation

Prior genetic testing guidance (29430) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 154

- Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice:

CDKN1C

Closing statement (29430) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 155

Simpson-Golabi-Behmel syndrome (11065)

Simpson-Golabi-Behmel syndrome eligibility (33717)

Level 3 Title Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders (10975)

Level 4 Title Simpson-Golabi-Behmel syndrome (11065)

Eligibility Relevant diseases: Statement • Simpson-Golabi-Behmel syndrome • Sotos syndrome • Weaver syndrome

Simpson-Golabi-Behmel syndrome inclusion criteria (33717) Clinical diagnosis of non-BWS overgrowth disorders (e.g. Sotos, Weaver, Simpson-Golabi-Behmel syndromes) without detectable germline mutation in relevant genes (e.g. EZH2, NSD1, GPC3).

Simpson-Golabi-Behmel exclusion criteria (33717)

Prior genetic testing guidance (33717) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Closing statement (33717) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 156

Sotos syndrome (11066)

Simpson-Golabi-Behmel syndrome eligibility (33717)

Level 3 Title Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders (10975)

Level 4 Title Sotos syndrome (11066)

Eligibility Relevant diseases: Statement • Simpson-Golabi-Behmel syndrome • Sotos syndrome • Weaver syndrome

Simpson-Golabi-Behmel exclusion criteria (33717)

Closing statement (33717) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 157

Weaver syndrome (11067)

Simpson-Golabi-Behmel syndrome eligibility (33717)

Level 3 Title Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders (10975)

Level 4 Title Weaver syndrome (11067)

Eligibility Relevant diseases: Statement • Simpson-Golabi-Behmel syndrome • Sotos syndrome • Weaver syndrome

Simpson-Golabi-Behmel exclusion criteria (33717)

Closing statement (33717) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 158

Growth restriction (38585)

Silver Russell syndrome (37553)

Silver Russell syndrome eligibility (37556)

Level 3 Title Growth restriction (38585)

Level 4 Title Silver Russell syndrome (37553)

Eligibility Statement Silver Russell syndrome inclusion criteria (37556) A. All 4 core features of Silver-Russell syndrome (SRS) present and no cause found B. 3 or more features present and family history of SRS or other imprinting disorder; or recurrent fetal loss with IUGR C. 3 or more features present and multilocus imprinting defect D. Isolated/single locus 11p15 methylation defect (H19 loss of methylation) with a family history of Silver- Russell syndrome.

Recruitment of relatives in these families should follow standard guidance.

E. Isolated/single locus 11p15 methylation defect (H19 loss of methylation) without a family history of Silver- Russell syndrome.

Recruitment to families in group D should occur only as proband-mother-father trios. Core clinical features of Silver-Russell syndrome: 1. small for gestational age (birth weight and/or length <-2SDS) +- history of intrauterine growth retardation; 2. post-natal short stature (<-2 SDS ) 3. body asymmetry 4. marked feeding difficulties in infancy / childhood +/- BMI 1.5 SDS relative to birth weight / length).

Silver Russell syndrome exclusion criteria (37556) • Other known short stature syndrome • Causative UPD (including UPD7, UPD14, UPD16, UPD20) • Causative chromosome rearrangement • Isolated methylation defect other than in familial cases

Prior genetic testing guidance (37556) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 159

sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Silver Russell syndrome prior genetic testing genes (37556) UPD7 testing and 11p15 methylation testing are required PRIOR TO RECRUITMENT as molecular diagnosis determines eligibility and methylation abnormalities cannot be detected on WGS.

Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice:

- Multi-locus methylation testing

Closing statement (37556) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 160

Haematological disorders (10977)

Anaemias and red cell disorders (10979)

Early onset pancytopenia and red cell disorders (11073)

Early onset pancytopenia and red cell disorders eligibility (29815)

Level 3 Title Anaemias and red cell disorders (10979)

Level 4 Title Early onset pancytopenia and red cell disorders (11073)

Eligibility Relevant diseases: Statement - Early onset pancytopenia and red cell disorders - Congenital anaemias

Early onset pancytopenia and red cell disorders inclusion criteria (29815) - Anaemia on more than one occasion

Early onset pancytopenia and red cell disorders exclusion criteria (29815) - Evidence that the anaemia is acquired (e.g. low B12, folate or ferritin or cytogenetic abnormalities)

Prior genetic testing guidance (29815) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Early onset pancytopenia and red cell disorders prior genetic testing genes (29815) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - As appropriate based on presentation - e.g. Sideroblastic anaemia ALAS2, SLC25A38; - Congenital Dyserythropoietic Anemia - C15orf41, CDAN1, GATA1

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 161

Closing statement (29815) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 162

Congenital anaemias (11075)

Congenital anaemias eligibility (29803)

Level 3 Title Anaemias and red cell disorders (10979)

Level 4 Title Congenital anaemias (11075)

Eligibility Relevant diseases: Statement - Early onset pancytopenia and red cell disorders - Congenital anaemias

Congenital anaemias inclusion criteria (29803) - Anaemia on more than one occasion

Congenital anaemias exclusion criteria (29803) - Evidence that the anaemia is acquired (e.g. low B12, folate or ferritin or cytogenetic abnormalities)

Prior genetic testing guidance (29803) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Congenital anaemias prior genetic testing genes (29803) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - As appropriate based on presentation - e.g. Sideroblastic anaemia - ALAS2, SLC25A38; - Congenital Dyserythropoietic Anemia - C15orf41, CDAN1, GATA1

Closing statement (29803) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 163

Apparent aplastic anaemia or paroxysmal nocturnal haemoglobinuria (33681)

Apparent aplastic anaemia or paroxysmal nocturnal haemoglobinuria eligibility (33481)

Level 3 Title Anaemias and red cell disorders (10979)

Level 4 Title Apparent aplastic anaemia or paroxysmal nocturnal haemoglobinuria (33681)

Eligibility Statement Apparent aplastic anaemia or paroxysmal nocturnal haemoglobinuria inclusion (33481) Aplastic anaemia • Bi-cytopenia or pancytopenia: at least 2 of 3 following: Hb <10g/dl, platelet count < 50 x 109/l, neutrophil count < 1.5 x 109/l, AND • Hypocellular bone marrow biopsy, AND • Normal MMC/DEB-induced (Fanconi anaemia)chromosome breakage result, AND • All cases must be discussed and approved by the aplastic anaemia/myeloid MDT at the recruiting GMC

Paroxysmal nocturnal haemoglobinuria (PNH) • Presence of PNH clone by flow cytometry, AND • All cases must be discussed and approved by the PNH/aplastic anaemia/myeloid MDT at the recruiting GMC

Apparent aplastic anaemia or paroxysmal nocturnal haemoglobinuria exclusion (33481) Aplastic anaemia • Abnormal infiltrate or fibrosis in bone marrow • B12 or folate deficiency • Known genetic cause already identified in proband or family member

Paroxysmal nocturnal haemoglobinuria • Absence of PNH clone by flow cytometry

Prior genetic testing guidance (33481) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 164

Apparent aplastic anaemia or paroxysmal nocturnal haemoglobinuria prior genetic testing genes (33481) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - Consideration of DKC1, PIGA, TERC, TERT, SBDS

Closing statement (33481) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 165

Immune dysregulation disorders (42205)

Familial haemophagocytic lymphohistiocytic disorders (41836)

Familial haemophagocytic lymphohistiocytic disorders eligibility (41840)

Level 3 Title Immune dysregulation disorders (42205)

Level 4 Title Familial haemophagocytic lymphohistiocytic disorders (41836)

Eligibility Statement Familial haemophagocytic lymphohistiocytic disorders inclusion criteria (41840) One of more episodes of HLH (at least 5/8 criteria as defined by the Histiocyte Society), AND An first, second or third degree relative with HLH or a related disorder (including dysgammaglobulinaemia, aplastic anaemia, lymphoma) AND at least one of the following: - Recurrent HLH (>4 weeks after initiating treatment for first episode) - Persistent HLH (no full remission can be achieved) - Partial albinism - At least one assay with absent degranulation (NK or CTL) or two assays with reduced degranulation

Standard nationally commissioned testing for this phenotype should have been completed: Perforin expression by flow cytometry; (males) SAP and XIAP protein expression by flow cytometry; degranulation assay (NK and T cells); blood film for neutrophil granules; hair microscopy

Familial haemophagocytic lymphohistiocytic disorders exclusion criteria (41840) Age >20 (unless familial) Known and secure diagnosis of systemic onset juvenile idiopathic arthritis or connective tissue disease, implying secondary HLH (macrophage activation syndrome)

Prior genetic testing guidance (41840) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 166

Familial haemophagocytic lymphohistiocytic disorders prior genetic testing genes (41840) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: Relevant genetic testing should be carried out as guided by the results of functional tests, this may include the targeted resequencing of the following: PRF1, SH2D1A, XIAP, STX11, STXBP2, UNC13D, LYST, RAB27A, AP3B1

Closing statement (41840) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 167

Primary immunodeficiency disorders (10978)

A- or hypo-gammaglobulinaemia (11068)

Primary immunodeficiency disorders eligibility (29434)

Level 3 Title Primary immunodeficiency disorders (10978)

Level 4 Title A- or hypo-gammaglobulinaemia (11068)

Eligibility Relevant diseases: Statement - A- or hypo-gammaglobulinaemia - Agranulocytosis - Congenital neutropaenia - SCID - Combined B and T cell defect

Primary immunodeficiency disorders inclusion criteria (29434) - Suspected primary immunodeficiency diagnosed by a consultant immunologist, particularly if familial. - Appropriate available diagnostic tests should have ruled out mutations in relevant known genes. - All cases must be discussed and approved by the PID-MDT at the recruiting GMC

Primary immunodeficiency disorders exclusion criteria (29434) - Known genetic cause already identified in proband or family member with similar phenotype. - Secondary immunodeficiency likely

Prior genetic testing guidance (29434) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Closing statement (29434)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 168

These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 169

Agranulocytosis (11069)

Primary immunodeficiency disorders eligibility (29434)

Level 3 Title Primary immunodeficiency disorders (10978)

Level 4 Title Agranulocytosis (11069)

Eligibility Relevant diseases: Statement - A- or hypo-gammaglobulinaemia - Agranulocytosis - Congenital neutropaenia - SCID - Combined B and T cell defect

Primary immunodeficiency disorders exclusion criteria (29434) - Known genetic cause already identified in proband or family member with similar phenotype. - Secondary immunodeficiency likely

Closing statement (29434) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 170

Combined B and T cell defect (11072)

Primary immunodeficiency disorders eligibility (29434)

Level 3 Title Primary immunodeficiency disorders (10978)

Level 4 Title Combined B and T cell defect (11072)

Eligibility Relevant diseases: Statement - A- or hypo-gammaglobulinaemia - Agranulocytosis - Congenital neutropaenia - SCID - Combined B and T cell defect

Primary immunodeficiency disorders exclusion criteria (29434) - Known genetic cause already identified in proband or family member with similar phenotype. - Secondary immunodeficiency likely

Closing statement (29434) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 171

Congenital neutropaenia (11070)

Primary immunodeficiency disorders eligibility (29434)

Level 3 Title Primary immunodeficiency disorders (10978)

Level 4 Title Congenital neutropaenia (11070)

Eligibility Relevant diseases: Statement - A- or hypo-gammaglobulinaemia - Agranulocytosis - Congenital neutropaenia - SCID - Combined B and T cell defect

Primary immunodeficiency disorders exclusion criteria (29434) - Known genetic cause already identified in proband or family member with similar phenotype. - Secondary immunodeficiency likely

Closing statement (29434) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 172

Inherited complement deficiency (33953)

Inherited complement deficiency eligibility (33477)

Level 3 Title Primary immunodeficiency disorders (10978)

Level 4 Title Inherited complement deficiency (33953)

Eligibility Statement Inherited complement deficiency inclusion criteria (33477) • Suspected complement deficiency diagnosed by a consultant immunologist/rheumatologist, AND • Clinical features suggestive of inherited complement deficiency such as early onset vasculitis and/or susceptibility to bacterial infections particularly Neisserial species, AND • Results of C3, C4, CH50, AP50 collected. Severely reduced or absent complement function as measured in an accredited diagnostic laboratory on at least two occasions, AND • All cases must be discussed and approved by the PID-MDT at the recruiting GMC

Inherited complement deficiency exclusion criteria (33477) • Secondary complement deficiency • Established genetic cause in proband or family member

Prior genetic testing guidance (33477) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Inherited complement deficiency prior genetic testing gene (33477) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice:

Closing statement (33477) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 173

SCID (11071)

Primary immunodeficiency disorders eligibility (29434)

Level 3 Title Primary immunodeficiency disorders (10978)

Level 4 Title SCID (11071)

Eligibility Relevant diseases: Statement - A- or hypo-gammaglobulinaemia - Agranulocytosis - Congenital neutropaenia - SCID - Combined B and T cell defect

Primary immunodeficiency disorders exclusion criteria (29434) - Known genetic cause already identified in proband or family member with similar phenotype. - Secondary immunodeficiency likely

Closing statement (29434) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 174

Hearing and ear disorders (10980)

Non-syndromic hearing loss (10981)

Congenital hearing impairment (11076)

Congenital hearing impairment eligibility (29442)

Level 3 Title Non-syndromic hearing loss (10981)

Level 4 Title Congenital hearing impairment (11076)

Eligibility Statement Congenital hearing impairment inclusion criteria (29442) Moderate or worse hearing loss that is congenital and/or prelingual, bilateral and apparently non-syndromic

Congenital hearing impairment exclusion criteria (29442) - Proven or suspected congenital CMV infection - Post-meningitis - Auditory neuropathy with concomitant neonatal hypoxia, jaundice, or prematurity

Prior genetic testing guidance (29442) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Congenital hearing impairment prior genetic testing genes (29442) Testing as below is strongly recommended PRIOR TO RECRUITMENT: - GJB2 (coding region plus splice site and GJB6 deletion); SLC26A4 if enlarged vestibular aqueducts

Closing statement (29442) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 175

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 176

Auditory Neuropathy Spectrum Disorder (30607)

Auditory Neuropathy Spectrum Disorder eligibility (30608)

Level 3 Title Non-syndromic hearing loss (10981)

Level 4 Title Auditory Neuropathy Spectrum Disorder (30607)

Eligibility Statement Auditory Neuropathy Spectrum Disorder inclusion criteria (30608) - Diagnosis of ANSD (based on evidence from ABR testing, OAEs and tympanometry) - Apparently non-syndromic - Completed Visual Evoked Potentials examination - Normal vestibulocochlear nerves and cochlear morphology on MRI scanning - Absence of clinically apparent peripheral neuropathy

Auditory Neuropathy Spectrum Disorder exclusion criteria (30608) - Prematurity (<37 weeks gestation or requiring >48 hours NICU ) - Severe jaundice - Known syndrome - Peripheral neuropathy

Prior genetic testing guidance (30608) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Auditory Neuropathy Spectrum Disorder prior genetic testing genes (30608) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - OPA1 if VEP prolonged

Closing statement (30608)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 177

These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 178

Autosomal dominant deafness (36848)

Autosomal dominant deafness eligibility (36860)

Level 3 Title Non-syndromic hearing loss (10981)

Level 4 Title Autosomal dominant deafness (36848)

Eligibility Statement Autosomal dominant deafness inclusion criteria (36860) • Non-syndromic hearing loss in proband, AND • Two or more additional affected family members in at least two generations, of which one must be a first degree relative of the proband and a have a similar or compatible audiometric hearing loss, AND • Audiometry must be provided on 2 or more affected individuals.

Autosomal dominant deafness exclusion criteria (36860) • Features of known syndrome

Prior genetic testing guidance (36860) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Autosomal dominant deafness prior genetic testing genes (36860) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - All patients must have dominant monoallelic or recessive bi-allelic mutations in GJB2 excluded - UKGTN gene panel testing is available and should be encouraged

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 179

Closing statement (36860) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 180

Deafness and congenital structural abnormalities (10982)

Bilateral microtia (11077)

Bilateral microtia eligibility (29446)

Level 3 Title Deafness and congenital structural abnormalities (10982)

Level 4 Title Bilateral microtia (11077)

Eligibility Statement Bilateral microtia inclusion criteria (29446) - Microtia affecting both ears (includes unilateral microtia with pre auricular tags or pits affecting the contralateral side) - Normal microarray - Ifpre auricularpits,renal scan and EYA1/SIX1 testing should be done

Bilateral microtia exclusion criteria (29446) - Maternal diabetes - Treacher-Collins syndrome and EFTUD2 clinically - The following syndromes should also be excluded clinically,unless mutationanalysishas been performed and is negative: LAMMsyndrome (labrytinthine aplasia, microtia and microdontia), BOR syndrome, BOF syndrome, Fraser syndrome, Miller syndrome, Nager syndrome, LADD syndrome, Meier Gorlin syndrome and Townes Brocks syndrome.

Prior genetic testing guidance (29446) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Bilateral microtia prior genetic testing genes (29446) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - Where the phenotype is recognisable and is caused by 1-2 principle genes, these should have been tested prior to recruitment

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 181

Closing statement (29446) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 182

Familial hemifacial microsomia (37649)

Familial hemifacial microsomia eligibility (37653)

Level 3 Title Deafness and congenital structural abnormalities (10982)

Level 4 Title Familial hemifacial microsomia (37649)

Eligibility Statement Familial hemifacial microsomia inclusion criteria (37653) • Proband with either HFM, Goldenhar or Oculoauriculovertebral spectrum, AND • At least two other relatives with features of first and second branchial arch anomalies especially macrostomia, epibulbar dermoid, asymmetric mandiular hypoplasia or microtia/ significant external ear anomaly (but not isolated preauricular pits or minor ear anomalies).

Familial hemifacial microsomia exclusion criteria (37653) • Known cause

Prior genetic testing guidance (37653) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Familial hemifacial microsomia prior genetic testing genes (37653) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: • aCGH or equivalent • Preauricular pits: EYA1, SIX1 • SALL1 (if abnormal thumbs or anal anomaly) • SALL4, EFTUD2 and SF3B4 (if abnormal thumbs) • TCOF1 (if bilateral microtia)

Closing statement (37653) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 183

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 184

Ear malformations with hearing impairment (37657)

Ear malformations with hearing impairment eligibility (37661)

Level 3 Title Deafness and congenital structural abnormalities (10982)

Level 4 Title Ear malformations with hearing impairment (37657)

Eligibility Statement Ear malformations with hearing impairment inclusion criteria (37661) • Unexplained bilateral ear malformation associated with bilateral hearing loss Examples include cochlear hypoplasia/aplasia, incomplete partitioning of the cochlea, dilated vestibule, dilated vestibular aqueducts, dilated, hypolplastic or absent semicircular canals, hypoplastic or absent VIIIth nerve, duplicated or absent IAM (internal auditory meatus).

Ear malformations with hearing impairment exclusion criteria (37661) • Bilateral lateral semicircular canal dysplasia is excluded.

Prior genetic testing guidance (37661) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Ear malformations with hearing impairment prior genetic testing genes (37661) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice:

• Enlarged vestibular aqueducts: SLC26A4 • Cochlear hypoplasia and preauricular pits in any family member: EYA1/SIX1 • Inner ear agenesis (absent cochlea or vestibule): FGF3 • Absent semi-circular canals: consider CHD7 • Vestibular/semicircular canal dysplasia: consider SOX10

Closing statement (37661)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 185

These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 186

Infectious diseases (42209)

Bacterial disorders (42210)

Disseminated non-tuberculous mycobacterial infection (41932)

Disseminated non-tuberculous mycobacterial infection eligibility (41936)

Level 3 Title Bacterial disorders (42210)

Level 4 Title Disseminated non-tuberculous mycobacterial infection (41932)

Eligibility Statement Disseminated non-tuberculous mycobacterial infection inclusion criteria (41936) Individuals with disseminated (multiple lymph nodes, liver, spleen, bone or other organs) or progressive disease (including progressive skin or lymph node infection at the site of BCG due to BCG or non-tuberculous mycobacteria

Disseminated non-tuberculous mycobacterial infection exclusion criteria (41936) Underlying immunodeficiency (PID, CGD); HIV Infection; Infection following bone marrow transplantation or cancer chemotherapy.

Prior genetic testing guidance (41936) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Disseminated non-tuberculous mycobacterial infection prior genetic testing genes (41936) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: No genes specified

Closing statement (41936)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 187

These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 188

Metabolic disorders (10983)

Specific metabolic abnormalities (10984)

Ketotic hypoglycaemia (11080)

Specific metabolic abnormalities eligibility (29455)

Level 3 Title Specific metabolic abnormalities (10984)

Level 4 Title Ketotic hypoglycaemia (11080)

Eligibility Specific metabolic abnormalities eligibility statements. Statement Specific Metabolic Abnormalities inclusion criteria (29455) - Evidence of inborn error of metabolism as demonstrated by findings in at least 2 of the following areas: - Clinical presentation - Biochemical - Haematological - Radiological - Biochemical testing and genetic testing completed for relevant known inborn errors of metabolism

Specific Metabolic Abnormalities exclusion criteria (29455)

Prior genetic testing guidance (29455) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Specific Metabolic Abnormalities prior genetic testing genes (29455) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - Genetic testing completed for relevant known inborn errors of metabolism

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 189

Closing statement (29455) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 190

Lactic acidosis (11081)

Specific metabolic abnormalities eligibility (29455)

Level 3 Title Specific metabolic abnormalities (10984)

Level 4 Title Lactic acidosis (11081)

Specific Metabolic Abnormalities exclusion criteria (29455)

Closing statement (29455) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 191

Cerebral folate deficiency (11083)

Specific metabolic abnormalities eligibility (29455)

Level 3 Title Specific metabolic abnormalities (10984)

Level 4 Title Cerebral folate deficiency (11083)

Specific Metabolic Abnormalities exclusion criteria (29455)

Closing statement (29455) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 192

Undiagnosed metabolic disorders (37620)

Undiagnosed metabolic disorders eligibility (37624)

Level 3 Title Specific metabolic abnormalities (10984)

Level 4 Title Undiagnosed metabolic disorders (37620)

Eligibility Statement Undiagnosed metabolic disorders inclusion criteria (37624) • Any patient seen in a metabolic clinic considered likely to have a monogenic disorder by a consultant Metabolic physician

Undiagnosed metabolic disorders exclusion criteria (37624)

Prior genetic testing guidance (37624) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Undiagnosed metabolic disorders prior genetic testing genes (37624) Genetic testing in line with current local practice should be considered in parallel with recruitment but is NOT required prior to recruitment.

Closing statement (37624) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 193

Congential disorders of glycosylation (37628)

Congential disorders of glycosylation eligibility (37632)

Level 3 Title Specific metabolic abnormalities (10984)

Level 4 Title Congential disorders of glycosylation (37628)

Eligibility Statement Congential disorders of glycosylation inclusion criteria (37632) • Repeated abnormal pattern on transferrin isolelectric focussing in a child of >3 months, AND • Clinically multisystem disease with abnormal protein C and / or S; AND Factor VIII and/or factor XI and /or ATIII (abnormal) OR • Muscle biopsy with abnormal dystroglycan pattern OR • Normal transferrin isolelectric focussing but patient thought to have CDG after assessment by metabolic or neurometabolic specialist and exclusion of abnormalities of VLCFA or 7DHC

Congential disorders of glycosylation exclusion criteria (37632) • Known genetic cause

Prior genetic testing guidance (37632) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Congential disorders of glycosylation prior genetic testing genes (37632) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: • Transferrin isoelectric focussing and, if abnormal, confirmed on a second sample and PMM2 deficiency excluded • Those with normal IEF should be assessed by metabolic or neurometabolic specialist for inclusion; 7DHC should be normal; VLCFA should be normal; protein C and S, factor VIII and XI and ATIII, T4 and TSH should be measured; for suspected isolated O glycosylation or combined N- and O-glycosylation defect ApoC III should be measured.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 194

Closing statement (37632) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 195

Urea Cycle disorders (15108)

Hyperammonaemia (11079)

Hyperammonaemia eligibility (29459)

Level 3 Title Urea Cycle disorders (15108)

Level 4 Title Hyperammonaemia (11079)

Eligibility Statement Hyperammonaemia inclusion criteria (29459) - Evidence of inborn error of metabolism as demonstrated by findings in at least 2 of the following areas: - Clinical presentation - Biochemical - Haematological - Radiological - Biochemical testing and genetic testing completed for relevant known inborn errors of metabolism

Hyperammonaemia exclusion criteria (29459)

Prior genetic testing guidance (29459) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Hyperammonaemia prior genetic testing genes (29459) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - Genetic testing completed for relevant known inborn errors of metabolism

Closing statement (29459) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 196

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 197

Lysosomal storage disorders (10985)

Mucopolysaccharideosis, Gaucher, Fabry (11084)

Mucopolysaccharideosis, Gaucher, Fabry eligibility (29463)

Level 3 Title Lysosomal storage disorders (10985)

Level 4 Title Mucopolysaccharideosis, Gaucher, Fabry (11084)

Eligibility Statement Mucopolysaccharideosis, Gaucher, Fabry inclusion criteria (29463) - Evidence of inborn error of metabolism as demonstrated by findings in at least 2 of the following areas: - Clinical presentation - Biochemical - Haematological - Radiological - Biochemical testing and genetic testing completed for relevant known inborn errors of metabolism

Mucopolysaccharideosis, Gaucher, Fabry exclusion criteria (29463)

Prior genetic testing guidance (29463) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Mucopolysaccharideosis, Gaucher, Fabry prior genetic testing genes (29463) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - Genetic testing completed for relevant known inborn errors of metabolism

Closing statement (29463) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 198

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 199

Mitochondrial (10986)

Mitochondrial disorders (11085)

Mitchondrial eligibility (29467)

Level 3 Title Mitochondrial (10986)

Level 4 Title Mitochondrial disorders (11085)

Eligibility Statement Mitochondrial inclusion criteria (29467) - Unexplained multi-system progressive disorder usually involving the central nervous system and/or neuromuscular system - Contributory laboratory findings may include but are not restricted to: - characteristic brain MR imaging, e.g. brainstem or basal ganglia involvement, infarction not confined to typical vascular territory, leukoencephalopathy - raised serum, CSF or urinary organic acid biomarkers (e.g. lactate, 3-MGA) - evidence of mitochondrial dysfunction in diagnostic biopsies including histochemical (COX-deficient fibres, ragged-red fibres) and biochemical (respiratory chain enzyme deficiencies) markers of disease pathology.

Mitcohondrial exclusion criteria (29467) - Mitochondrial DNA and common nuclear genetic causes (e.g. POLG) excluded (m.3243A>G, POLG)

Prior genetic testing guidance (29467) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Mitcohondrial prior genetic testing genes (29467) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - Mitochondrial DNA - Common nuclear genetic causes as appropriate

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 200

Closing statement (29467) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 201

Peroxisomal disorders (10987)

Peroxisomal biogenesis disorders (11086)

Peroxisomal eligibility (29471)

Level 3 Title Peroxisomal disorders (10987)

Level 4 Title Peroxisomal biogenesis disorders (11086)

Eligibility Statement Peroxisoomal inclusion criteria (29471) - Evidence of inborn error of metabolism as demonstrated by findings in at least 2 of the following areas: - Clinical presentation - Biochemical - Haematological - Radiological - Biochemical testing and genetic testing completed for

Peroxisomal exclusion criteria (29471)

Prior genetic testing guidance (29471) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Peroxisomal Prior Testing prior genetic testing genes (29471) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - Genetic testing completed for relevant known inborn errors of metabolism

Closing statement (29471) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 202

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 203

Other peroxisomal disorders (15109)

Peroxisomal eligibility (29471)

Level 3 Title Peroxisomal disorders (10987)

Level 4 Title Other peroxisomal disorders (15109)

Peroxisomal exclusion criteria (29471)

Closing statement (29471) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 204

Disorders of extremely low weight , severe familial anorexia (15110)

Severe familial anorexia (29278)

Severe familial anorexia eligibility (29475)

Level 3 Title Disorders of extremely low weight , severe familial anorexia (15110)

Level 4 Title Severe familial anorexia (29278)

Eligibility Statement Severe familial anorexia inclusion criteria (29475) - Anorexia nervosa restricting or binge/purge type - Duration of >5 years - At least one first- or two second- degree relative affected - Minimum BMI of 16 kg/m2 - Maintenance of low BMI - Other indices of starvation may be present such as amenorrhea (in women), lanugo, bradycardia, hypotension, hypoleptinemia,

The optimal family structure for Severe familial anorexia is to recruit the affected proband, their parents, and any affected siblings; outside this structure, no other unaffected relatives should be recruited.

Severe familial anorexia exclusion criteria (29475) - Acute onset after head injury - Primary Adrenal insufficiency, Crohns, inflammatory bowel disease, cealiac disease, ulcerative colitis

Prior genetic testing guidance (29475) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Severe familial anorexia prior genetic testing genes (29475) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice:

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 205

No genes listed

Closing statement (29475) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 206

Neurology and neurodevelopmental disorders (10988)

Motor Disorders of the CNS (10989)

Cerebellar hypoplasia (36512)

Cerebellar hypoplasia eligibility (36515)

Level 3 Title Motor Disorders of the CNS (10989)

Level 4 Title Cerebellar hypoplasia (36512)

Eligibility Statement Cerebellar hypoplasia inclusion criteria (36515) • Cerebellar or ponto-cerebellar hypoplasia on MRI brain scan

Cerebellar hypoplasia exclusion criteria (36515) • Findings characteristic of Joubert syndrome (in which case recruit to Joubert syndrome category) • Known genetic cause • Evidence of causative prenatal infection such as CMV (this usually causes more widespread brain abnormalities such as calcification not just cerebellar hypoplasia)

Prior genetic testing guidance (36515) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Cerebellar hypoplasia prior genetic testing genes (36515) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - Gene panel including ITPR1, SPTBN2, KCNC3, CASK, OPHN1

Closing statement (36515)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 207

These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 208

Hereditary ataxia (11087)

Hereditary ataxia eligibility (29480)

Level 3 Title Motor Disorders of the CNS (10989)

Level 4 Title Hereditary ataxia (11087)

Eligibility Statement Hereditary ataxia inclusion criteria (29480) - Unexplained cerebellar ataxia progressing over >2 years +/- spasticity, peripheral neuropathy, or bulbar dysfunction.

Individuals with syndromic disease or disease onset <30 years should be recruited according to standard guidance, typically as trios. Disease status of apparently unaffected participants should be determined according to standard clinical practice to detect cryptic disease.

Hereditary ataxia exclusion criteria (29480) - No structural or inflammatory (MS-like) lesions on brain MRI. - No history of alcohol excess. - Normal thyroid function. - No evidence of malignancy.

Prior genetic testing guidance (29480) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Hereditary ataxia prior genetic testing genes (29480) Testing for genes which are affected by trinucleotide repeats is strongly recommended PRIOR TO RECRUITMENT as these will not be reliably detected by WGS using current analysis techniques including:

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 209

- Common trinucleotide repeat disorders excluded (ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, TBP, ATN1, FXN (only recessive history), FMR1

Closing statement (29480) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 210

Early onset dystonia (11088)

Early onset dystonia eligibility (29483)

Level 3 Title Motor Disorders of the CNS (10989)

Level 4 Title Early onset dystonia (11088)

Eligibility Statement Early onset dystonia inclusion criteria (29483) - Dystonia affecting any body part, usually spreading to involve multiple body regions (e.g. multifocal, segmental, generalised) - Age at onset <31 years or later onset with family history of early onset dystonia - May be paroxysmal/episodic dystonia - May be associated with myoclonus as in myoclonic dystonia

This disease category includes dopa responsive dystonia.

Early onset dystonia exclusion criteria (29483) - Underlying cause for clinical syndrome identified, e.g. cerebral palsy, dopa-responsive dystonia, structural brain lesion, Wilson disease, psychogenic dystonia

Prior genetic testing guidance (29483) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Early onset dystonia prior genetic testing genes (29483) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - TOR1A

Closing statement (29483) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 211

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 212

Hereditary spastic paraplegia (11089)

Hereditary spastic paraplegia eligibility (29490)

Level 3 Title Motor Disorders of the CNS (10989)

Level 4 Title Hereditary spastic paraplegia (11089)

Eligibility Statement Hereditary spastic paraplegia inclusion criteria (29490) - Unexplained spastic paraplegia progressing over >2 years +/-, peripheral neuropathy, or ataxia. Individuals with syndromic disease or disease onset <30 years should be recruited according to standard guidance, typically as trios. Disease status of apparently unaffected participants should be determined according to standard clinical practice to detect cryptic disease. In other cases, unaffected individuals should not be recruited. Recruitment in such families should favour multiplex families over single isolated cases. These singleton recruits will not contribute to the overall singleton monitoring metrics applied to GMCs.

Hereditary spastic paraplegia exclusion criteria (29490) - No structural or inflammatory (MS-like) lesions on brain MRI.

Prior genetic testing guidance (29490) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Hereditary spastic paraplegia prior genetic testing genes (29490) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - SPG4, SPG3A - Normal very long chain fatty acid studies

Closing statement (29490) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 213

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 214

Neurotransmitter disorders (37779)

Neurotransmitter disorders eligibility (37782)

Level 3 Title Motor Disorders of the CNS (10989)

Level 4 Title Neurotransmitter disorders (37779)

Eligibility Statement Neurotransmitter disorders inclusion criteria (37782) • Patient with an abnormal CSF neurotransmitter profile indicating an abnormal HVA, HIAA or pterin profile • Patients with symptoms suspicious of dopamine/serotonin deficiency (e.g. movement disorder, gait abnormalities, hypotonia, autonomic features and neurodevelopmental delay)

Neurotransmitter disorders exclusion criteria (37782) • CSF neurotransmitter highly suggestive of a primary neurotransmitter that would warrant exclusion of this condition e.g. a CSF profile consistent with AADC deficiency would warrant AADC enzyme activity and DDC genetic testing before patient would be eligible • Normal CSF neurotransmitter profile • No clinical features of a neurotransmitter disorder

Prior genetic testing guidance (37782) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Neurotransmitter disorders prior genetic testing genes (37782) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice:

• As determined by CSF profile

Closing statement (37782) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 215

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 216

Structural basal ganglia disorders (37786)

Structural basal ganglia disorders eligibility (37789)

Level 3 Title Motor Disorders of the CNS (10989)

Level 4 Title Structural basal ganglia disorders (37786)

Eligibility Statement Structural basal ganglia disorders inclusion criteria (37789) • Patient with structural, preferably symmetrical radiological abnormalities on MR imaging affecting the striatum, globus pallidus and/or substantia nigra, AND • Neurological symptoms e.g. movement disorder

Structural basal ganglia disorders exclusion criteria (37789) • Evidence of an acquired disorder (e.g. basal ganglia stroke or autoimmune aetiology) • No neurological symptoms • Known genetic cause

Prior genetic testing guidance (37789) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Structural basal ganglia disorders prior genetic testing genes (37789) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice:

- As dictated by phenotype

Closing statement (37789) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 217

Inherited Epilepsy Syndromes (10990)

Genetic Epilepsies with Febrile Seizures Plus (11091)

Genetic Epilepsies with Febrile Seizures Plus eligibility (29494)

Level 3 Title Inherited Epilepsy Syndromes (10990)

Level 4 Title Genetic Epilepsies with Febrile Seizures Plus (11091)

Eligibility Statement Genetic Epilepsies with Febrile Seizures Plus inclusion criteria (29494) Families with:

- autosomal dominant inheritance (with at least 2 first degree family members or 3 generations affected) - electrographically-proven generalised seizures, which may, or may not be associated with intellectual impairment; and febrile seizures or febrile seizures plus; AND where: - focal seizures form are a minor part of the family phenotype

Genetic Epilepsies with Febrile Seizures Plus exclusion criteria (29494) - SCN1A positive; - No family history of febrile seizures (recruit under familial GGE); - No family history of generalised seizure disorder; - Suspected acquired cause of epilepsy based on history or imaging; - Previously identified genetic cause of epilepsy

Prior genetic testing guidance (29494) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Closing statement (29494)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 218

These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 219

Familial Genetic Generalised Epilepsies (11092)

Familial Genetic Generalised Epilepsies eligibility (29502)

Level 3 Title Inherited Epilepsy Syndromes (10990)

Level 4 Title Familial Genetic Generalised Epilepsies (11092)

Eligibility Statement Familial Genetic Generalised Epilepsies inclusion criteria (29502) - Electrographically-proven generalised epilepsy - At least two first degree relatives or affected family members across three generations who have generalised epilepsy - All forms of generalised epilepsy are permissible

Familial Genetic Generalised Epilepsies exclusion criteria (29502) - Suspected acquired cause of epilepsy - Focal neurological deficit - MRI demonstrates structural substrate for epilepsy - EEG demonstrates definite focal discharges

Prior genetic testing guidance (29502) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Closing statement (29502) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 220

Familial Focal Epilepsies (11093)

Familial Focal Epilepsies eligibility (29505)

Level 3 Title Inherited Epilepsy Syndromes (10990)

Level 4 Title Familial Focal Epilepsies (11093)

Eligibility Statement Familial Focal Epilepsies inclusion criteria (29505) - Patients with focal epilepsy not thought to be acquired in aetiology - At least two first degree relatives or affected family members across three generations who have focal epilepsy that is not thought to be acquired in aetiology - All forms of focal epilepsy are permissible

Familial Focal Epilepsies exclusion criteria (29505) - Suspected acquired cause of epilepsy - EEG demonstrates definite generalised epileptiform discharges

Prior genetic testing guidance (29505) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Closing statement (29505) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 221

Epileptic encephalopathy (11094)

Epileptic encephalopathy eligibility (29508)

Level 3 Title Inherited Epilepsy Syndromes (10990)

Level 4 Title Epileptic encephalopathy (11094)

Eligibility Statement Epileptic encephalopathy inclusion criteria (29508) - Recurrent seizures with onset of epilepsy prior to two years of age AND - Negative genome wide microarray copy number analysis

Epileptic encephalopathy exclusion criteria (29508) - Major structural brain malformation such as cortical malformation, neuronal migration defect AND/OR - Known clear biochemical, enzymatic or molecular genetic evidence of underlying metabolic cause, e.g. organic aciduria, vitamin B6 metabolism defect

Prior genetic testing guidance (29508) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Closing statement (29508) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 222

Epilepsy plus other features (41924)

Epilepsy plus other features eligibility (41928)

Level 3 Title Inherited Epilepsy Syndromes (10990)

Level 4 Title Epilepsy plus other features (41924)

Eligibility Statement Epilepsy plus other features inclusion criteria (41928) Established diagnosis of epilepsy, confirmed by a neurologist

AND with at least one additional phenotype from: intellectual disability, autism spectrum disorder, structural abnormality (e.g. dysmorphism, cerebral or somatic malformation), unexplained cognitive/memory decline

OR Consanguineous parents

Epilepsy plus other features exclusion criteria (41928) Case falls into one of the other GeL epilepsy disease categories Focal, unilateral cerebral malformations

Prior genetic testing guidance (41928) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Epilepsy plus other features prior genetic testing genes (41928) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: As dictated by local practice and clinical phenotype including consideration of SCN1A

Closing statement (41928) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 223

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 224

Motor and Sensory Disorders of the PNS (10991)

Charcot-Marie-Tooth disease (15111)

Charcot-Marie-Tooth disease eligibility (29512)

Level 3 Title Motor and Sensory Disorders of the PNS (10991)

Level 4 Title Charcot-Marie-Tooth disease (15111)

Eligibility Statement Charcot-Marie-Tooth disease inclusion criteria (29512) - Unexplained peripheral neuropathy affecting motor, sensory or autonomic nerves progressing over >2 years +/- additional neurological signs.

Charcot-Marie-Tooth disease exclusion criteria (29512) - History of trauma - Known acquired metabolic, vascular, inflammatory or immunological cause - History of alcohol excess - Evidence of malignancy - ENG/EMG suggest acquired pathology

Prior genetic testing guidance (29512) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Charcot-Marie-Tooth disease prior genetic testing genes (29512) Testing for the chromosome 17p11.2 duplication is strongly recommended PRIOR TO RECRUITMENT as this may not be reliably detected by WGS using current analysis techniques; other tests below should be considered where this is in line with current local practice including: - PMP22 point mutations, GJB1, MPZ, MFN2 (MFN2 axonal only)

Closing statement (29512)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 225

These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 226

Paediatric motor neuronopathies (11099)

Paediatric motor neuronopathies eligibility (29519)

Level 3 Title Motor and Sensory Disorders of the PNS (10991)

Level 4 Title Paediatric motor neuronopathies (11099)

Eligibility Relevant diseases: Statement - Brown-Vialetto-Van Laere syndrome - Spinal muscular atrophy with respiratory distress - Fazio-Londe syndrome

Paediatric motor neuronopathies inclusion criteria (29519) - Bulbar palsy +/- sensorineural deafness, visual impairment, seizures, motor and/or global developmental delay - Congenital or presentation in early childhood most commonly (presentation can occur in adult life, but is rare) - Full neurometabolic screen completed with normal/inconclusive findings - EMG consistent with bulbar palsy +/- evidence of more extensive motor neuron involvement

Paediatric motor neuronopathies exclusion criteria (29519)

Prior genetic testing guidance (29519) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Closing statement (29519) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 227

Neurodegenerative disorders (10992)

Early onset and familial Parkinson's Disease (11100)

Early onset and familial Parkinson's Disease eligibility (29525)

Level 3 Title Neurodegenerative disorders (10992)

Level 4 Title Early onset and familial Parkinson's Disease (11100)

Eligibility Statement Early onset and familial Parkinson's Disease inclusion criteria (29525) - Early onset (<= 45 years of age) or history of other family member with Parkinson’s Disease - Bradykinesia plus at least one of rigidity, rest tremor and gait disturbance - May have concurrent dystonia (common in early onset PD) - May have positive family history or consanguinity - If complex features, e.g. spasticity, early dementia, gaze palsy, Neurodegeneration with Brain Iron Accumulation, please recruit to Complex Parkinsonism - May develop Lewy Body/PD type dementia

Early onset and familial Parkinson's Disease exclusion criteria (29525) - Underlying cause for clinical syndrome identified, e.g. cerebral palsy, dopa-responsive dystonia, structural brain lesion, Wilson disease, psychogenic dystonia

Prior genetic testing guidance (29525) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 228

Early onset and familial Parkinson's Disease prior genetic testing genes (29525) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: LRRK2 G2019S (dominant), PARK2 (parkin, recessive) and PINK1 (recessive). Clinical phenotype and family history to guide testing.

Closing statement (29525) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 229

Complex Parkinsonism (includes pallido-pyramidal syndromes) (15112)

Complex Parkinsonism eligibility (29529)

Level 3 Title Neurodegenerative disorders (10992)

Level 4 Title Complex Parkinsonism (includes pallido-pyramidal syndromes) (15112)

Eligibility Statement Complex Parkinsonism inclusion criteria (29529) - Progressive motor syndrome with parkinsonism (bradykinesia with one of tremor, gait disorder, stiffness) - Additional features may include spasticity, gaze palsy, early dementia, early bulbar failure, dyspraxia, ataxia, postural hypotension, cortical sensory loss, brain iron accumulation on MRI brain - Age at onset <= 45 years or later onset with family history of similar condition in other family members

Complex Parkinsonism exclusion criteria (29529) - Underlying cause not identified, e.g. structural brain lesion, Wilson disease

Prior genetic testing guidance (29529) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Complex Parkinsonism prior genetic testing genes (29529) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - C9ORF72, GRN, MAPT in cases with a clinical presentation suggestive of cortico-basal/PSP syndrome

Closing statement (29529)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 230

These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 231

Early onset dementia (encompassing fronto-temporal dementia and prion disease) (15113)

Early onset dementia eligibility (29533)

Level 3 Title Neurodegenerative disorders (10992)

Level 4 Title Early onset dementia (encompassing fronto-temporal dementia and prion disease) (15113)

Eligibility Statement Early onset dementia inclusion criteria (29533) - Progressive cognitive deterioration with change in memory, vision, behaviour or language with functional impairment - Age at onset <50 years OR - Later onset with family history of dementia of the same type in a first or second degree relative

Early onset dementia exclusion criteria (29533) - Identified underlying cause, e.g. structural brain lesion. NB in uncertain cases with anxiety/depression brain atrophy on imaging, CSF findings or EEG abnormalities should be available to support the diagnosis of a primary degenerative syndrome

Prior genetic testing guidance (29533) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Early onset Dementia prior genetic testing genes (29533) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - Clinical syndrome Alzheimer disease: PSEN1, APP - Clinical syndrome FTLD: MAPT, C9ORF72, GRN

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 232

- Clinical syndrome Prion disease: PRNP

Closing statement (29533) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 233

Amyotrophic lateral sclerosis or motor neuron disease (15114)

Amyotrophic lateral sclerosis or motor neuron disease eligibility (29537)

Level 3 Title Neurodegenerative disorders (10992)

Level 4 Title Amyotrophic lateral sclerosis or motor neuron disease (15114)

Eligibility Statement Amyotrophic lateral sclerosis or motor neuron disease inclusion criteria (29537) - Progressive upper and/or lower motor neuron disease degeneration with clinical features of amyotrophy, spasticity, bulbar/pseudo-bulbar involvement - EMG/NCS consistent with MND - Positive family history of other affected family members with ALS or with FTD/ALS like phenotype or disease onset below 40 years.

Amyotrophic lateral sclerosis or motor neuron disease exclusion criteria (29537) - Identified underlying cause for clinical syndrome e.g. multi-focal motor neuropathy, lymphoma

Prior genetic testing guidance (29537) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Amyotrophic lateral sclerosis or motor neuron disease prior genetic testing genes (29537) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - C9ORF72, SOD1

Closing statement (29537)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 234

These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 235

Neurodevelopmental disorders (10993)

Classical tuberous sclerosis (11101)

Classical tuberous sclerosis eligibility (29542)

Level 3 Title Neurodevelopmental disorders (10993)

Level 4 Title Classical tuberous sclerosis (11101)

Eligibility Statement Classical tuberous sclerosis inclusion criteria (29542) 2 major or 1 major and >=2 minor criteria:

- Major features - Hypomelanotic macules (>=3 at least 5-mm diameter) - Angiofibromas (>=3) or fibrous cephalic plaque - Ungual fibromas (>=2) - Shagreen patch - Multiple retinal hamartomas - Cortical dysplasias (tubers or cerebral white matter radial migration lines) - Subependymal nodules - Subependymal giant cell astrocytoma - Cardiac rhabdomyoma - Lymphangioleiomyomatosis (LAM) - Renal angiomyolipomas (>=2)

- Minor features - Confetti skin lesions - Dental enamel pits (>3) - Intraoral fibromas (>=2) - Retinal achromic patch - Multiple renal cysts - Nonrenal hamartomas

AND - Participants who have not undergone prior genetic testing of TSC1 and TSC2 should be recruited initially as singletons. In families where analysis as a singleton does not lead to identification of the underlying causative mutation, recruitment of additional affected family members is encouraged.

Classical tuberous sclerosis exclusion criteria (29542)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 236

Prior genetic testing guidance (29542) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Classical tuberous sclerosis prior genetic testing genes (29542) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: TSC1, TSC2

Closing statement (29542) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 237

Intellectual disability (11102)

Intellectual disability eligibility (29546)

Level 3 Title Neurodevelopmental disorders (10993)

Level 4 Title Intellectual disability (11102)

Eligibility NB. Clinical test guidance: Statement Imaging diagnostsics refers to MRI brain and/or medical photographs of facial features and other physical features as appropriate

Intellectual disability inclusion criteria (29546) - Moderate to Severe/ Profound ID disproportionate to parental IQ unless the family history is consistent with an X- linked disorder - Congenital onset - Developmental Delay - +/- clinical features suggestive of a specific syndrome - Metabolic causes have been excluded

Intellectual disability exclusion criteria (29546) - Antenatal history suggestive of non-genetic cause - Proven congenital or neonatal infections - Known genetic cause already identified - Microarray analysis abnormal and clearly pathogenic

Prior genetic testing guidance (29546) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Intellectual disability prior genetic testing genes (29546) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - For syndromes where the cause of disease is 1-2 genes these need to be excluded before Genomics England recruitment, e.g. for Kabuki syndrome, MLL2 (KMT2D) and KDM6A should have been tested

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 238

Closing statement (29546) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 239

Holoprosencephaly (36519)

Holoprosencephaly eligibility (36522)

Level 3 Title Neurodevelopmental disorders (10993)

Level 4 Title Holoprosencephaly (36519)

Eligibility Statement Holoprosencephaly inclusion criteria (36522) Holoprosencephaly: one major and one minor Major: • 1. Holoprosencephaly • 2. Single central incisor Minor: • 1. Unilateral or bilateral choanal stenosis/atresia • 2. Ptosis • 3. Small head circumference • 4. Learning difficulties • 5. Dysmorphic features • 6. Hypopituitarism

Holoprosencephaly exclusion criteria (36522) Chromosome rearrangement consistent with the diagnosis

Prior genetic testing guidance (36522) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Holoprosencephaly prior genetic testing genes (36522) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - Genome-wide copy number variation testing (e.g. aCGH, SNP array or other genomic microarray)

Closing statement (36522)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 240

These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 241

Rhomboencephalosynapsis (36603)

Rhomboencephalosynapsis eligibility (36606)

Level 3 Title Neurodevelopmental disorders (10993)

Level 4 Title Rhomboencephalosynapsis (36603)

Eligibility Statement Rhomboencephalosynapsis inclusion criteria (36606) Rhombencephalosynapsis • 1. MRI findings indivative of rhombencephalosynapsis reviewed by an experienced neuroradiologist

Rhomboencephalosynapsis exclusion criteria (36606) Chromosome rearrangement consistent with the diagnosis

Prior genetic testing guidance (36606) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Rhomboencephalosynapsis prior genetic testing genes (36606) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - Genome-wide copy number variation testing (e.g. aCGH, SNP array or other genomic microarray)

Closing statement (36606) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 242

Malformations of cortical development (36526)

Malformations of cortical development eligibility (36529)

Level 3 Title Neurodevelopmental disorders (10993)

Level 4 Title Malformations of cortical development (36526)

Eligibility Statement Malformations of cortical development inclusion criteria (36529) • Evidence of diffuse or focal cortical brain malformation on brain MRI or pathology, AND • MCD the cardinal feature, AND • Appropriate known gene, if testing available via UKGTN, excluded , AND • Congenital infection, especially CMV, has been excluded if suggested by phenotype

Malformations of cortical development exclusion criteria (36529) • Brain MRI or pathology not available • Known genetic cause • Evidence of congenital infection • Known metabolic condition • Raised CK levels indicative of muscle-eye-brain disease • Diagnosis of Tuberous Sclerosis • MCD clearly part of a known MCA syndrome with a known cause • Fetal cases – these should be recruited to the fetal structural brain anomaly category

Prior genetic testing guidance (36529) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Malformations of cortical development prior genetic testing genes (36529) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - 1. Microarray - 2. Exclusion of PAFAH1B1 and DCX gene deletions using MLPA or similar method where appropriate. - 3. Single MCD gene or MCD gene panel testing as guided by phenotype.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 243

Closing statement (36529) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 244

Fetal structural CNS abnormalities (36850)

Fetal structural CNS abnormalities eligibility (36869)

Level 3 Title Neurodevelopmental disorders (10993)

Level 4 Title Fetal structural CNS abnormalities (36850)

Eligibility Statement Fetal structural CNS abnormalities inclusion criteria (36869) Neuronal migration abnormality: Bilateral neuronal migration abnormality, confirmed on MRI or pathology, normal TORCH screen Posterior fossa abnormality: Cerebellar vermis agenesis /hypoplasia < 5th percentile and / or bilateral cerebellar hemisphere hypoplasia /atrophy Midline brain abnormalities: Absent cavum septum pellucidum or holoprosencephaly or complete / partial agenesis of the corpus callosum Severe ventriculomegaly with posterior ventricle measuring > 15mm: non-obstructive, normal spine anatomy, normal TORCH screen Microcephaly: Head circumference measuring <3rd percentile, normal TORCH & VZV screen. For all: Both parents MUST be available to provide a blood sample for testing.

Fetal structural CNS abnormalities exclusion criteria (36869) Midline brain abnormalities: maternal exposure to illicit drugs and alcohol Severe ventriculomegaly: intracranial haemorrhage of any underlying cause; twin pregnancy related problems. Microcephaly: Parental head circumference measuring <3rd percentile, normal HC/AC and HC/FL ratios. For all: A known genetic or chromosomal cause.

Prior genetic testing guidance (36869) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Fetal structural CNS abnormalities prior genetic testing genes (36869) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice:

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 245

• chromosome microarray • ASPM and other genes dictated by the phenotype

Closing statement (36869) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 246

Neuromuscular disorders (10994)

Congenital muscular dystrophy (15135)

Congenital muscular dystrophy eligibility (29550)

Level 3 Title Neuromuscular disorders (10994)

Level 4 Title Congenital muscular dystrophy (15135)

Eligibility Relevant diseases: Statement - Congenital muscular dystrophy

Congenital muscular dystrophy inclusion criteria (29550) - Muscle weakness with onset in infancy or early childhood AND - elevated creatine kinases or muscle biopsy with dystrophic changes - Availability of CK and muscle biopsy results - Dystrophic changes on muscle biopsy

Congenital muscular dystrophy exclusion criteria (29550)

Prior genetic testing guidance (29550) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Closing statement (29550) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 247

Congenital myopathy (11103)

Congenital myopathy eligibility (29553)

Level 3 Title Neuromuscular disorders (10994)

Level 4 Title Congenital myopathy (11103)

Eligibility Relevant diseases: Statement - Congenital myopathy

Congenital myopathy inclusion criteria (29553) - Muscle weakness - ne or more of the following histopathological features - type 1 predominance or uniformity - congenital fibre type disproportion - central cores - multi-minicores - nemaline rods - central nuclei

- Availability of CK, muscle CT/MR imaging, muscle biopsy and neurophysiological studies

Congenital myopathy exclusion criteria (29553) - Absence of muscle weakness - CK more than 5x normal - dystrophic features on muscle biopsy

Prior genetic testing guidance (29553) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Closing statement (29553)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 248

These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 249

Congenital myaesthenia (15136)

Congenital myaesthenia eligibility (29556)

Level 3 Title Neuromuscular disorders (10994)

Level 4 Title Congenital myaesthenia (15136)

Eligibility Statement Congenital myaesthenia inclusion criteria (29556) - Patients at any age with fatigable weakness and fluctuating motor symptoms - Clinical neurophysiology revealing a neuromuscular transmission defect (repetitive nerve stimulation, or Single fibre EMG) - Review of patient data by CMS NHS Highly Specialised Services for Rare Diseases service

Congenital myaesthenia exclusion criteria (29556) - Response to immunosuppressive treatment - Presence of anti- AChR or MuSK antibodies - Muscle biopsy indicative of mitochondrial disorder. Muscle biopsy giving clear indication of dystrophy or other muscle disorder

Prior genetic testing guidance (29556) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Closing statement (29556) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 250

Rhabdomyolysis and metabolic muscle disorders (15137)

Rhabdomyolysis and metabolic muscle disorders eligibility (29559)

Level 3 Title Neuromuscular disorders (10994)

Level 4 Title Rhabdomyolysis and metabolic muscle disorders (15137)

Eligibility Statement Rhabdomyolysis and metabolic muscle disorders inclusion criteria (29559) - At least 2 of the criteria listed below: - Symptom triggers: Exercise, fasting, fever and heat - Variable CK with exacerbations >10x above basal value - Myoglobinuria (tea or coca cola coloured urine) - In patient treatment for acute rhabdomyolysis with or without acute renal failure - Muscle weakness is progressive - Usually muscle pain associated with atrophy and weakness - Malignant Hyperpyrexia syndrome - Neuroleptic Malignant syndrome - Acute compartment Syndrome Individuals with severe or syndromic disease should be recruited according to standard guidance, typically as trios. Disease status of apparently unaffected participants should be determined according to standard clinical practice to detect cryptic disease. In other cases, unaffected individuals should not be recruited. Recruitment in such families should favour multiplex families over single isolated cases. These singleton recruits will not contribute to the overall singleton monitoring metrics applied to GMCs.

Rhabdomyolysis and metabolic muscle disorders exclusion criteria (29559) - Non exercise related limb pain - Muscle biopsy with histochemical enzyme or sarcolemmal protein deficiencies to indicate a diagnosis of GSDV, GSDVII or muscular dystrophy (Becker or LGMD) - Abnormal fasting blood acyl carnitines and/or urine organic acids consistent with a known FAODD - Confirmed viral induced myositis without myoglobinuria - Prescribed (e.g. statin) or recreational drug triggers - Severe trauma

Prior genetic testing guidance (29559) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 251

Closing statement (29559) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 252

Distal myopathies (11104)

Distal myopathies eligibility (29562)

Level 3 Title Neuromuscular disorders (10994)

Level 4 Title Distal myopathies (11104)

Eligibility Statement Distal myopathies inclusion criteria (29562) - Unexplained predominantly distal muscle weakness, onset at any age - Acquired myopathies excluded by relevant clinical investigations - Serum creatine kinase (CK) assessment - Muscle Biopsy with immunohistochemistry (IH) - Neurophysiology performed - Muscle MRI (optional) - Dried blood spot test for Pompe disease performed

Distal myopathies exclusion criteria (29562)

Prior genetic testing guidance (29562) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Distal myopathies prior genetic testing genes (29562) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - DMD MLPA - FSHD1 and DM1 exclusion by conventional genetic testing - Exclusion by genetic testing of any gene indicated by IH. - In the presence of evidence of myofibrillar myopathy on muscle biopsy IH exclusion of ZASP, MYOT, DES, CRYAB by sequencing

Closing statement (29562)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 253

These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 254

Arthrogryposis (15138)

Arthrogryposis eligibility (29571)

Level 3 Title Neuromuscular disorders (10994)

Level 4 Title Arthrogryposis (15138)

Eligibility Statement Arthrogryposis inclusion criteria (29571) - Multiple congenital bilateral joint contractures - EMG/NCV completed - Creatinine kinase measured - MRI brain if developmentally delayed or otherwise clinically indicated - TORCH screen if developmentally delayed and less than 6 months old - Maternal anti-acetylcholine receptor antibodies - Consideration of skeletal survey to exclude skeletal dysplasia

Arthrogryposis exclusion criteria (29571) - Isolated talipes/clubfoot - Oligohydramnios - Major structural CNS abnormalities likely to be causative of phenotype - Confident clinical diagnosis of amyoplasia

Prior genetic testing guidance (29571) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Arthrogryposis prior genetic testing genes (29571) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice:

- If associated with other abnormalities, genome-wide copy number variation testing (e.g. aCGH, SNP array or other genomic microarray)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 255

Closing statement (29571) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 256

Limb girdle muscular dystrophy (11106)

Limb girdle muscular dystrophy eligibility (29567)

Level 3 Title Neuromuscular disorders (10994)

Level 4 Title Limb girdle muscular dystrophy (11106)

Eligibility Statement Limb girdle muscular dystrophy inclusion criteria (29567) - Unexplained predominantly proximal muscle weakness, onset at any age. - Acquired myopathies excluded by relevant clinical investigations. - Serum creatine kinase (CK) assessment. - Muscle Biopsy with immunohistochemistry (IH) performed. - Dried blood spot test for Pompe disease performed. - Muscle MRI (optional). - Review of patient data by LGMD NHS Highly Specialised Services for Rare Diseases service

Limb girdle muscular dystrophy exclusion criteria (29567) - Phenotypes suggestive of FSHD, DM1 or DM2.

Prior genetic testing guidance (29567) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Limb girdle muscular dystrophy prior genetic testing genes (29567) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - DMD MLPA, LMNA, ANO5, CAPN3 and FKRP by sequencing. - Exclusion by genetic testing of any gene indicated by IH.

Closing statement (29567) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 257

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 258

Channelopathies (11097)

Skeletal Muscle Channelopathies (15139)

Skeletal Muscle Channelopathies eligibility (29575)

Level 3 Title Channelopathies (11097)

Level 4 Title Skeletal Muscle Channelopathies (15139)

Eligibility Statement Skeletal Muscle Channelopathies inclusion criteria (29575) - Episodic flaccid paralysis or weakness and/or myotonia - May develop progressive, usually proximal, weakness - Electrophysiology including long and short exercise testing - Intra-attack potassium documented whenever possible - Normal renal function and thyroid function

Skeletal Muscle Channelopathies exclusion criteria (29575) - Primary renal or endocrine problem that may be causative - Associated loss of consciousness with attacks

Prior genetic testing guidance (29575) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Skeletal Muscle Channelopathies prior genetic testing genes (29575) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - Myotonia: DMPK, CNBP, SCN4A, CLCN1 (including MLPA) - Episodic weakness: CACNA1S, SCN4A, KCNJ2

Closing statement (29575)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 259

These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 260

Brain channelopathy (15140)

Brain channelopathy eligibility (29579)

Level 3 Title Channelopathies (11097)

Level 4 Title Brain channelopathy (15140)

Eligibility Statement Brain channelopathy inclusion criteria (29579) - Episodic disorder that often causes a combination of ataxia with walking problems, abnormal extra movements, stiff legs, weakness, headache and nausea. - Episodes lasting a few minutes or hours. - There may be a dystonic component and some patients are exhausted for many hours afterwards. - Attacks are not always the same, even with the same genetic defect. - Arms can be affected like legs - Migraine type headaches are frequently associated as is dysarthria - Some patients have a primary headache in the form of hemiplegic migraine (FHM), cluster headache, SUNCT or SUNA - MRI brain and cord to exclude common causes such as tumours, discs, demyelinating causes - Family history of often present in AD or AR forms, X linked pattern rare - Often drugs such as Lamotrigine or acetazolamide are effective

Brain channelopathy exclusion criteria (29579)

Prior genetic testing guidance (29579) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 261

Brain channelopathy prior genetic testing genes (29579) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - KCNA1, PRRT2 as appropriate - CACNA1A (only in dominant, long duration episodic ataxia)

Closing statement (29579) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 262

Sleep disorders (10995)

Kleine-Levin syndrome and other inherited sleep disorders (11108)

Kleine-Levin syndrome and other inherited sleep disorders eligibility (29583)

Level 3 Title Sleep disorders (10995)

Level 4 Title Kleine-Levin syndrome and other inherited sleep disorders (11108)

Eligibility NB. Clinical test guidance: Statement Imaging diagnostics refers to Brain MRI

Kleine-Levin syndrome and other inherited sleep disorders inclusion criteria (29583) -Recurrent hypersomnia: -Recurrent episodes of excessive daytime sleepiness lasting for 2 days-4 weeks -Episodes recur at least once per year -Alertness, cognitive function and behavior are normal between episodes -Hypersomnia -AND at least 1 of the following: -Cognitive abnormalities – ex confusion, derealisation(“déjà vu” during episodes, dream-like state or experiencing out of body hallucinations -Abnormal behaviour – irritability, aggression -Hyperphagia OR -Recurrent daytime hypersomnia: -Sudden onset of sleep or "sleep attacks" -Other symptoms can include cataplexy, hypnagogic hallucinations and Sleep paralysis -A positive family history OR -Involuntary kicking and jerking movements of the legs and arms often repeated 100s of times during the night -Unaware of their multiple night-time awakenings unless they are witnessed by a bed partner -In extreme cases these brief arousals following the leg movements disturb sleep so much that they cause excessive daytime sleepiness -A +ve family history OR -The symptoms of parasomnias: -Sleepwalking—takes place during deep sleep, not REM sleep when dreams typically occur -Night terrors—these severe attacks cause people, usually children, to appear to wake up and scream in fear or panic -Sleep-eating disorders—these episodes occur during partial awakenings from deep sleep and cause individuals to eat without any knowledge of what they are doing. -A +ve family history Individuals with severe or syndromic disease should be recruited according to standard

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 263

guidance, typically as trios. Disease status of apparently unaffected participants should be determined according to standard clinical practice to detect cryptic disease. In other cases, unaffected individuals should not be recruited. Recruitment in such families should favour multiplex families over single isolated cases. These singleton recruits will not contribute to the overall singleton monitoring metrics applied to GMCs.

Kleine-Levin syndrome and other inherited sleep disorders exclusion criteria (29583) - No structural or inflammatory (MS-like) lesions on brain MRI. - No atypical depression - No sleep disorders (exclude Narcolepsy and Menstruation-related hypersomnia) - No substance abuse (particularly benzodiazepine) - No temporal lobe epilepsy - Metabolic Encephalopathy - Lyme disease - Acute intermittent porphyria

Prior genetic testing guidance (29583) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Closing statement (29583) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 264

Cerebrovascular disorders (36610)

Moyamoya disease (36611)

Moyamoya disease eligibility (36614)

Level 3 Title Cerebrovascular disorders (36610)

Level 4 Title Moyamoya disease (36611)

Eligibility Statement Moyamoya disease inclusion criteria (36614) • Bilateral intracranial occlusive arteriopathy, with or without basal collaterals, confirmed by review by an expert neuroradiologist

Moyamoya disease exclusion criteria (36614)

Prior genetic testing guidance (36614) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Moyamoya disease prior genetic testing genes (36614) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: No genes listed

Closing statement (36614) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 265

Vein of Galen malformation (42174)

Vein of Galen malformation eligibility (42178)

Level 3 Title Cerebrovascular disorders (36610)

Level 4 Title Vein of Galen malformation (42174)

Eligibility Statement Vein of Galen malformation inclusion criteria (42178) Vein of Galen malformation diagnosed by an expert neuroradiologist

Vein of Galen malformation exclusion criteria (42178) Vein of Galen aneurysmal dilatation Other brain AVM

Prior genetic testing guidance (42178) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Vein of Galen malformation prior genetic testing genes (42178) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: No genes specified

Closing statement (42178) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 266

Parenchymal brain disorders (36618)

Intracerebral calcification disorders (36619)

Intracerebral calcification disorders eligibility (36622)

Level 3 Title Parenchymal brain disorders (36618)

Level 4 Title Intracerebral calcification disorders (36619)

Eligibility Statement Intracerebral calcification disorders inclusion criteria (36622) • Intracerebral calcification identified on brain imaging in the absence of a known genetic cause.

Intracerebral calcification disorders exclusion criteria (36622) • Known genetic diagnosis. • Evidence of causative environmental cause, for example infection • Phenotype indicative of other recruitable rare disorder, for example Cockayne syndrome

Prior genetic testing guidance (36622) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Intracerebral calcification disorders prior genetic testing genes (36622) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - Guided by phenotype, for example UKGTN Aidcardi-Goutieres syndrome gene panel testing

Closing statement (36622) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 267

White matter disorders (36626)

Inherited white matter disorders (36627)

Inherited white matter disorders eligibility (36630)

Level 3 Title White matter disorders (36626)

Level 4 Title Inherited white matter disorders (36627)

Eligibility Statement Inherited white matter disorders inclusion criteria (36630) • Patients with a proven or suspected inherited white mater disorder on the basis of abnormal white matter on MR imaging reviewed by an expert neuroradiologist. • Relevant metabolic investigations completed, for example very long chain fatty acids, white cell enzymes and urine organic acids where indicated

Inherited white matter disorders exclusion criteria (36630) • Known genetic cause • Evidence of causative environmental cause, for example infection, hypoxia or inflammation • Phenotype indicative of other recruitable rare disorder, for example Cockayne syndrome or intracerebral calcification indicative of Aicardi-Goutiere’s syndrome, or a peroxisomal disorder, in which case recruit to relevant category

Prior genetic testing guidance (36630) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Inherited white matter disorders prior genetic testing genes (36630) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - Guided by phenotype, for example PLP1 in males with a phenotype suggestive of Pelizaeus-Merzbacher disease or GJA1 in the presence of phenotypic features of oculodentodigital dysplasia.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 268

Closing statement (36630) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 269

Ophthalmological disorders (10996)

Anterior segment abnormalities (10997)

Corneal abnormalities (11110)

Corneal abnormalities eligibility (29586)

Level 3 Title Anterior segment abnormalities (10997)

Level 4 Title Corneal abnormalities (11110)

Eligibility Statement Corneal abnormalities inclusion criteria (29586) - Bilateral corneal signs - Prior consultation with ophthalmologist who has a specialist interest in corneal dystrophies

Corneal abnormalities exclusion criteria (29586) - Corneal opacity likely secondary to inflammatory disease or trauma (including surgical) - Age-related corneal endothelial failure - Keratoconus

Prior genetic testing guidance (29586) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Corneal abnormalities prior genetic testing genes (29586) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - TGFBI (BIGH3) gene screening in anterior corneal dystrophies (which accounts for approximately 80% of such families)

Closing statement (29586)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 270

These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 271

Glaucoma (developmental) (11111)

Glaucoma eligibility (29590)

Level 3 Title Anterior segment abnormalities (10997)

Level 4 Title Glaucoma (developmental) (11111)

Eligibility Statement Glaucoma inclusion criteria (29590) - Diagnosis of developmental glaucoma confirmed (preferably) by an ophthalmologist with a sub-specialist expertise in childhood glaucoma - Availability of relevant phenotypic information including: - structural assessment of anterior segment - optic nerve head characteristics - intraocular pressure at first presentation - highest ever recorded IOP, where available - slit lamp assessment of anterior segment - pachymetry - ERG and VEP (if appropriate) - Availability of non-ocular phenotypic information if appropriate: - Presence/absence of maxillary hypoplasia - umbilical anomaly - cardiac anomalies (from history) - growth delay - dental anomalies - metabolic disease (from history)

Glaucoma exclusion criteria (29590) - Features of adult-onset glaucoma - Suggestion of secondary (acquired) glaucoma, i.e. following trauma, intraocular neoplasm, uveitis, lens-related (subluxation, spherophakia, phacolytic), following lensectomy, drug-induced (corticosteroids), secondary to rubeosis, angle closure, associated with increased venous pressure, or following intraocular infection.

Prior genetic testing guidance (29590) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

PLEASE NOTE: The sensitivity of WGS compared to current diagnostic genetic testing has not yet been established.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 272

It is therefore important that tests which are clinically indicated under local standard practice continue to be carried out.

Glaucoma prior genetic testing genes (29590) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - MYOC in cases of juvenile open angle glaucoma - CYP1B1 in cases of primary congenital glaucoma - PAX6 in cases of aniridia

Closing statement (29590) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 273

Cataracts (11112)

Cataracts eligibility (29594)

Level 3 Title Anterior segment abnormalities (10997)

Level 4 Title Cataracts (11112)

Eligibility Statement Cataracts inclusion criteria (29594) - Congenital cataracts, or cataracts diagnosed in childhood - Bilaterally affected individuals - Isolated or complex

Cataracts exclusion criteria (29594)

Prior genetic testing guidance (29594) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Closing statement (29594) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 274

Posterior segment abnormalities (10998)

Inherited optic neuropathies (11114)

Inherited optic neuropathies eligibility (29597)

Level 3 Title Posterior segment abnormalities (10998)

Level 4 Title Inherited optic neuropathies (11114)

Eligibility Statement Inherited optic neuropathies inclusion criteria (29597) - Optic atrophy occurring either in isolation or in association with other multisystemic features - Evidence of optic nerve dysfunction on clinical examination - Additional objective evidence of primary retinal ganglion cell dysfunction with optical coherence tomography imaging and/or visual electrophysiology performed to ISCEV standards

Inherited optic neuropathies exclusion criteria (29597) - Acquired causes of an optic neuropathy have been fully excluded with the relevant investigations, including neuroimaging - Optic atrophy secondary to inherited outer retinal disease

Prior genetic testing guidance (29597) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Inherited optic neuropathies prior genetic testing genes (29597) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - Testing for mitochondrial DNA mutations

Closing statement (29597)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 275

These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 276

Rod-cone dystrophy (29268)

Rod-cone dystrophy eligibility (29601)

Level 3 Title Posterior segment abnormalities (10998)

Level 4 Title Rod-cone dystrophy (29268)

Eligibility Statement Rod-cone dystrophy inclusion criteria (29601) - Retinal degeneration as shown by decreased rod / cone responses on an ISCEV ERG and / or clear phenotypic evidence of retinal degeneration as shown by clinical features, e.g. retinal bone spicules, retinal thinning on OCT scans, typical visual field defects such as mid peripheral retinal scotoma. - Evidence of bilateral retinal degeneration.

Rod-cone dystrophy exclusion criteria (29601) - History of retinal detachment or an inflammatory process (e.g. syphilis or tuberculosis infection) masquerading as unilateral retinal degeneration.

Prior genetic testing guidance (29601) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Closing statement (29601) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 277

Rod Dysfunction Syndrome (29269)

Rod Dysfunction Syndrome eligibility (29604)

Level 3 Title Posterior segment abnormalities (10998)

Level 4 Title Rod Dysfunction Syndrome (29269)

Eligibility Relevant diseases: Statement - Poor night vision from infancy / early childhood with no evidence of progression - Congenital stationary night blindness - Oguchi disease - Åland Island eye disease - Fundus albipunctatus

Rod Dysfunction Syndrome inclusion criteria (29604) - Presentation from infancy / early childhood including some of these features: nystagmus, reduced visual acuity, and poor night vision. - ISCEV standard ERG has been performed. - Normal fundus appearance except for fundus albipunctatus (multiple discrete white dots scattered throughout the retina at the level of the RPE - most numerous in the mid-periphery and are usually absent at the macula) and Oguchi disease (greyish or green-yellow discoloration of the fundus, which reverts to normal on prolonged dark adaptation)

Rod Dysfunction Syndrome exclusion criteria (29604)

Prior genetic testing guidance (29604) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Closing statement (29604) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 278

Cone Dysfunction Syndrome (29270)

Cone Dysfunction Syndrome eligibility (29608)

Level 3 Title Posterior segment abnormalities (10998)

Level 4 Title Cone Dysfunction Syndrome (29270)

Eligibility Relevant diseases: Statement - Complete achromatopsia - Incomplete achromatopsia - Blue cone monochromatism - Oligocone trichromacy - Bradyopsia - Borholm eye disease

Cone Dysfunction Syndrome exclusion criteria (29608)

Cone Dysfunction Syndrome inclusion criteria (29608) - Absent or severely reduced cone function from birth / early infancy with no significant evidence of rod involvement. - Presentation from birth / early infancy ÔÇô including some of these features: nystagmus, photophobia, reduced visual acuity, and reduced/absent colour vision. - Absent or severely reduced cone function with no significant rod dysfunction on ISCEV standard ERGs - Assessment of colour vision using tests that probe the 3 axes of colour

Prior genetic testing guidance (29608) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Closing statement (29608) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 279

Inherited macular dystrophy (29271)

Inherited macular dystrophy eligibility (29615)

Level 3 Title Posterior segment abnormalities (10998)

Level 4 Title Inherited macular dystrophy (29271)

Eligibility - Available phenotype data including ISCEV ERG, OCT and AF imaging Statement - Diagnosis confirmed preferably by an ophthalmologist with a sub-specialist expertise in inherited retinal disease.

Inherited macular dystrophy inclusion criteria (29615) - Available phenotype data including ISCEV ERG, OCT and AF imaging - Diagnosis confirmed preferably by an ophthalmologist with a sub-specialist expertise in inherited retinal disease.

Inherited macular dystrophy exclusion criteria (29615) - Features of age-related macular degeneration ( any two of - onset over 60 years, soft drusen, CNV, RPE atrophy) - Features of readily testable single gene disorders such as Doyne/dominant drusen (p.R345W in EFEMP1), Best (dominant or recessive alleles in BEST1), RDS (typical macular dystrophy associated with such alleles as p.R172W in RDS). These phenotypes are eligible if there is evidence of negative testing of the associated gene. - Unilateral disease - Suggestion of chloroquine, hydroxychlorquine or other retinotoxic drug aetiology - Signs suggestive of an inflammatory aetiology such as toxocara, toxoplasmosis.

Prior genetic testing guidance (29615) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Inherited macular dystrophy prior genetic testing genes (29615) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - EFEMP1 in cases of Doyne/dominant drusen - BEST1 in cases of Best macular dystrophy - PRPH2 (RDS) in cases of typical macular dystrophy

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 280

Closing statement (29615) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 281

Leber Congenital Amaurosis or Early-Onset Severe Retinal Dystrophy (29272)

Leber Congenital Amaurosis or Early-Onset Severe Retinal Dystrophy eligibility (29619)

Level 3 Title Posterior segment abnormalities (10998)

Level 4 Title Leber Congenital Amaurosis or Early-Onset Severe Retinal Dystrophy (29272)

Eligibility Relevant diseases: Statement - Leber Congenital Amaurosis (LCA) - Early-Onset Severe Retinal Dystrophy (EOSRD)

Leber Congenital Amaurosis or Early-Onset Severe Retinal Dystrophy inclusion criteria (29619) - Severe disorders in which there is progressive loss of rod and later cone photoreceptor function leading to severe visual impairment - Usually occurring as an isolated retinal abnormality but can be syndromic (e.g. Joubert syndrome, peroxisomal disorders, and Senior-Loken syndrome) - LCA: presentation from birth / early infancy with nystagmus, absence / marked reduction in pupillary responses, and severely reduced vision. ISCEV ERG undetectable or severely reduced. - EOSRD: presentation within the first 5 years of life with reduced visual acuity, poor night vision, and markedly reduced ISCEV ERG with greater rod than cone system involvement.

Leber Congenital Amaurosis or Early-Onset Severe Retinal Dystrophy exclusion criteria (29619)

Prior genetic testing guidance (29619) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Closing statement (29619) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 282

Developmental macular and foveal dystrophy (29273)

Developmental macular and foveal dystrophy eligibility (29634)

Level 3 Title Posterior segment abnormalities (10998)

Level 4 Title Developmental macular and foveal dystrophy (29273)

Eligibility Statement Developmental macular and foveal dystrophy inclusion criteria (29634) - Absence of the fovea (synonym foveal hypoplasia - defined by preservation of inner retinal layers throughout the macula) OR - Congenital abnormality of the macula such as that seen in North Carolina Macular dystrophy, Bifocal chorioretinopathy and Sorsby syndrome OR - Congenital foveal retinoschisis

Developmental macular and foveal dystrophy exclusion criteria (29634) - Foveal retinoschisis compatible with XL RS1 disease in a male (unless screened negative for RS1 mutations - Unilateral disease - Signs suggestive of an inflammatory aetiology such as toxocara and toxoplasmosis

Prior genetic testing guidance (29634) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Developmental macular and foveal dystrophy prior genetic testing genes (29634) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - GPR143 if foveal hypoplasia is in the context of albinism confined to the eye and there is an X-linked history or typical carrier signs - PAX6 if foveal hypoplasia is in the context of aniridia - RS1 in males with foveal schisis

Closing statement (29634)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 283

These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 284

Familial exudative vitreoretinopathy (41900)

Familial exudative vitreoretinopathy eligibility (41904)

Level 3 Title Posterior segment abnormalities (10998)

Level 4 Title Familial exudative vitreoretinopathy (41900)

Eligibility Statement Familial exudative vitreoretinopathy inclusion criteria (41904) All probands should be diagnosed with bilateral retinopathy consistent with familial exudative vitreoretinopathy following detailed retinal examination and include at least one of the following features: - peripheral retinal avascularity (preferably demonstrated through fluorescein angiography) - subretinal or intraretinal exudation - retinal detachment - neovascularisation with or without vitreous haemorrhage

Examination of parents, when available to distinguish recessive disease from dominant disease with variable expressivity.

Individuals with severe or syndromic disease should be recruited according to standard guidance, typically as trios.

Familial exudative vitreoretinopathy exclusion criteria (41904) Birth weight below 1500g or under 32 weeks gestational age at birth. Unilateral retinopathy Localised retinal telangiectasia Coat's disease Peripheral angiomatous retinal malformation

Prior genetic testing guidance (41904) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 285

carried out.

Familial exudative vitreoretinopathy prior genetic testing genes (41904) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: No genes specified

Closing statement (41904) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 286

Ocular malformations (10999)

Anophthalmia or microphthamia (11115)

Anophthalmia eligibility (29638)

Level 3 Title Ocular malformations (10999)

Level 4 Title Anophthalmia or microphthamia (11115)

Eligibility Relevant diseases: Statement - Anophthalmia/microphthalmia

Anophthalmia (clinical absence of the eye) and severe microphthalmia (congenital reduction in the overall size of the globe) represent clinically significant inborn errors of early development.

Anophthalmia inclusion criteria (29638) - Unilateral or bilateral anophthalmia or microphthalmia

Anophthalmia exclusion criteria (29638)

Prior genetic testing guidance (29638) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Anophthalmia prior genetic testing genes (29638) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - Genome-wide copy number variation (e.g. aCGH, SNP array or other genomic microarray) - SOX2, OTX2 (severe, bilateral cases)

Closing statement (29638)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 287

These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 288

Ocular coloboma (15141)

Ocular coloboma eligibility (29645)

Level 3 Title Ocular malformations (10999)

Level 4 Title Ocular coloboma (15141)

Eligibility Statement Ocular coloboma inclusion criteria (29645) - Ocular coloboma taken to represent failure of the optic fissure to close with awide spectrum of clinical severity asa consequence of variation in the site and extent of the closure defect. - Unilateral or bilaterally affected individuals.

Ocular coloboma exclusion criteria (29645)

Prior genetic testing guidance (29645) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Closing statement (29645) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 289

Ocular movement disorders (33350)

Infantile nystagmus (33662)

Infantile nystagmus eligibility (33485)

Level 3 Title Ocular movement disorders (33350)

Level 4 Title Infantile nystagmus (33662)

Eligibility Statement Infantile nystagmus inclusion criteria (33485) • Nystagmus with onset in early infancy, AND • Normal ophthalmological examination with normal VEP and ERG

Infantile nystagmus exclusion criteria (33485) • Anterior segment disorders • Retinal dystrophies • Abnormal ERG and VEP • Acquired nystagmus • Grade 2 to 4 foveal hypoplasia • Structural abnormality found on MRI brain scan

Prior genetic testing guidance (33485) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Infantile nystagmus prior genetic testing genes (33485) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: FRMD7 unless inheritance through paternal line

Closing statement (33485)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 290

These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 291

Renal and urinary tract disorders (11000)

Syndromes with prominent renal abnormalities (11001)

Proteinuric renal disease (30732)

Proteinuric renal disease eligibility (30735)

Level 3 Title Syndromes with prominent renal abnormalities (11001)

Level 4 Title Proteinuric renal disease (30732)

Eligibility Statement Proteinuric renal disease inclusion criteria (30735) - Urinary protein:creatinine ratio >100 mg/mmol OR albumin:creatinine ratio >30 mg/mmol on 2 or more occasions over more than 1 month AND - Family history of renal failure or proteinuria by the above criteria AND - Kidney biopsy in at least one family member showing focal segmental glomerulosclerosis (FSGS), focal global glomerulosclerosis, diffuse mesangial sclerosis (DMS), membranous glomerulopathy or isolated podocyte foot process effacement OR - Familial steroid sensitive nephrotic syndrome, OR - glycosuria, low molecular weight proteinuria, aminoaciduria, vitamin B12 deficiency or other evidence of proximal tubular dysfunction

Proteinuric renal disease exclusion criteria (30735) - Orthostatic proteinuria - Proteinuria present only within 6 months of pregnancy - Proteinuric renal disease attributable to obesity or systemic disorder (including but not limited to: diabetes mellitus, SLE or other autoimmune disease, infection, malignancy, paraproteinaemia, amyloidosis, Fabry disease, cystinosis, drugs etc) - Proteinuria or FSGS secondary to other identified primary renal disorder (e.g. MPGN, IgA nephropathy etc)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 292

Prior genetic testing guidance (30735) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Proteinuric renal disease prior genetic testing genes (30735) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - No gene accounts for >10% of cases. Consideration of sequencing with (UKGTN approved) SRNS gene panel of 33 genes, which detected a mutation in ~20% of cases.

Closing statement (30735) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 293

Familial haematuria (30733)

Familial haematuria eligibility (30743)

Level 3 Title Syndromes with prominent renal abnormalities (11001)

Level 4 Title Familial haematuria (30733)

Eligibility Statement Familial haematuria inclusion criteria (30743) - Persistent microscopic haematuria AND one or both of: - Family history of kidney failure or microscopic haematuria - Kidney biopsy showing characteristic electron micrographic features of Alport syndrome or thin glomerular basement membrane nephropathy

Familial haematuria exclusion criteria (30743) - Known or suspected renal or urinary tract malignancy - Known or suspected renal calculi - Known monogenic cause of microscopic haematuria

Prior genetic testing guidance (30743) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Familial haematuria prior genetic testing genes (30743) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: COL4A3, COL4A4 and COL4A5 where indicated by the phenotype.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 294

Closing statement (30743) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 295

Atypical haemolytic uraemic syndrome (33489)

Atypical haemolytic uraemic syndrome eligibility (33528)

Level 3 Title Syndromes with prominent renal abnormalities (11001)

Level 4 Title Atypical haemolytic uraemic syndrome (33489)

Eligibility Statement Atypical haemolytic uraemic syndrome inclusion criteria (33528) • Renal biopsy showing a thrombotic microangiopathy, OR • the classic triad of microangiopathic haemolytic anaemia, thrombocytopenia, renal failure.

Atypical haemolytic uraemic syndrome exclusion criteria (33528) • Shiga toxin associated HUS • Secondary causes – drugs, infection (HIV, Streptococcus pneumonia), transplantation (bone marrow, liver, lung, cardiac but not de-novo renal), cobalamin deficiency, SLE, APL Ab syndrome, scleroderma • ADAMTS13 activity <10% or anti-ADAMTS13 autoantibodies

Prior genetic testing guidance (33528) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Atypical haemolytic uraemic syndrome prior genetic testing genes (33528) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: CFH, CFI, CD46

Closing statement (33528) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 296

Structural renal and urinary tract disease (11003)

Cystic kidney disease (11120)

Cystic kidney disease eligibility (29656)

Level 3 Title Structural renal and urinary tract disease (11003)

Level 4 Title Cystic kidney disease (11120)

Eligibility Statement Cystic kidney disease inclusion criteria (29656) - >5 cysts affecting one or both kidneys AND - Unaffected individuals have undergone appropriate screening for cryptic disease e.g. renal ultrasound scan - Individuals with severe or syndromic disease should be recruited according to standard guidance, preferably as trios - In other cases, unaffected individuals should not be recruited. Recruitment in such families should favour multiplex families over single isolated cases. These singleton recruits will not contribute to the overall singleton monitoring metrics applied to GMCs. AND - Participants with features suggestive of classical ADPKD (autosomal dominant polycystic kidney disease) who have not undergone prior genetic testing of PKD1 and PKD2 should be recruited initially as singletons. In families where analysis as a singleton does not lead to identification of the underlying causative mutation, recruitment of additional affected family members is encouraged.

Cystic kidney disease exclusion criteria (29656) - Advanced or end-stage kidney failure due to identified (non-cystic) disease - Multicystic dysplastic kidney(s) (see CAKUT)

Prior genetic testing guidance (29656) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 297

Cystic kidney disease prior genetic testing genes (29656) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: PKD1 and PKD2 if kidneys enlarged for age (or >12cm in length in adults). PKHD1 if family history and phenotype consistent with AR PKD. These genes need not be tested if other phenotypic features make them unlikely to be causative.

Closing statement (29656) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 298

Congenital Anomaly of the Kidneys and Urinary Tract (CAKUT) (29277)

CAKUT eligibility (29660)

Level 3 Title Structural renal and urinary tract disease (11003)

Level 4 Title Congenital Anomaly of the Kidneys and Urinary Tract (CAKUT) (29277)

Eligibility Statement CAKUT inclusion criteria (29660) A. One or more of: - Renal hypodysplasia or agenesis - Congenital multicystic kidney - Congenital, persistent, severe hydroureter - Congenital, persistent, severe congenital hydronephrosis - Bladder exstrophy - Posterior urethral valves In the presence or absence of family history or other features OR B. One or more of: - Duplex kidney - Vesicoureteric reflux - Vesicoureteric or ureteropelvic junction obstruction AND - Syndromic disease OR - Family history of CAKUT AND (for A. or B.) - Unaffected individuals have undergone appropriate investigation for cryptic disease e.g. renal ultrasound scan - Individuals with severe or syndromic disease should be recruited according to standard guidance, preferably as trios - In other cases, unaffected individuals should not be recruited. Recruitment in such families should favour multiplex families over single isolated cases. These singleton recruits will not contribute to the overall singleton monitoring metrics applied to GMCs.

CAKUT exclusion criteria (29660) - Clinical or molecular diagnosis of autosomal dominant or autosomal recessive polycystic kidney disease - Known causative genetic or chromosomal abnormality

Prior genetic testing guidance (29660) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 299

CAKUT prior genetic testing genes (29660) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - HNF1B if personal or family history of diabetes mellitus - SALL1 if 2 out of imperforate anus, ear abnormalities, thumb abnormalities

Closing statement (29660) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 300

Disorders of function (11004)

Renal tubular acidosis (11123)

Renal tubular acidosis eligibility (29664)

Level 3 Title Disorders of function (11004)

Level 4 Title Renal tubular acidosis (11123)

Eligibility Relevant diseases: Statement - Distal renal tubular acidosis - Renal Fanconi syndrome - Gitelman and Bartter type 3 syndrome (Hypokalaemic alkalosis with hypomagnesaemia & hypocalcalciuria) - Bartter syndrome type 1, 2 & 4 (Hypokalaemic alkalosis with hypercalciuria) - Liddle syndrome (hypertensive hypokalaemic alkalosis) - Gordon syndrome (hypertensive hyperkalaemic acidosis) - Glucocorticoid remediable hypertension - Apparent Mineralocorticoid excess - Pseudohypoaldosteronism type1

Renal tubular acidosis inclusion criteria (29664) - Renal acid-base or other electrolyte disorders of unknown aetiology. AND - Unaffected individuals have undergone appropriate screening for cryptic disease - Individuals with severe or syndromic disease should be recruited according to standard guidance, preferably as trios - In other cases, unaffected individuals should not be recruited. Recruitment in such families should favour multiplex families over single isolated cases. These singleton recruits will not contribute to the overall singleton monitoring metrics applied to GMCs.

Renal tubular acidosis exclusion criteria (29664) - Prior genetic testing that identifies a pathogenic mutation in a gene known to cause one or more of the diseases detailed above.

Prior genetic testing guidance (29664) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 301

Renal tubular acidosis prior genetic testing genes (29664) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - Distal renal tubular acidosis: SLC4A1, ATP6V0A4, ATP6V1B1 - Hypokalaemic alkalosis with hypomagnesaemia & hypocalciuria: SLC12A3, CLCNKB - Hypokalaemic alkalosis with hypercalciuria: SLC12A1, KCNJ1, BSND

Closing statement (29664) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 302

Renal tract calcification (or Nephrolithiasis or nephrocalcinosis) (11124)

Renal tract calcification eligibility (29668)

Level 3 Title Disorders of function (11004)

Level 4 Title Renal tract calcification (or Nephrolithiasis or nephrocalcinosis) (11124)

Eligibility Statement Renal tract calcification inclusion criteria (29668) - Nephrolithiasis or nephrocalcinosis AND one or more of: - Age of first episode under 21 - Positive family history of stones/nephrocalcinosis in first or second degree relative - Hyper/hypocalcaemia - Abnormal PTH in setting of normal eGFR - Metabolic acidosis/alkalosis - Hypercalciuria - Hyperphosphaturia - Hyperoxaluria - Aminoaciduria - Hypocitraturia - Hypermagnesuria AND - Unaffected individuals have undergone appropriate screening for cryptic disease e.g. renal ultrasound scan, AND Individuals with severe or syndromic disease should be recruited according to standard guidance, preferably as trios - In other cases, unaffected individuals should not be recruited. Recruitment in such families should favour multiplex families over single isolated cases. These singleton recruits will not contribute to the overall singleton monitoring metrics applied to GMCs.

Renal tract calcification exclusion criteria (29668) - Excluding infection stones

Prior genetic testing guidance (29668) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 303

carried out.

Renal tract calcification prior genetic testing genes (29668) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - AGXT, GRHPR, HOGA1 if Hyperoxaluria - ATP6V1B1, ATP6V0A4, SLC4A1 if distal renal tubular acidosis - SLC3A1, SLC7A9 if cystinuria - CASR if hypocalciuric hypercalcaemia

Closing statement (29668) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 304

Extreme early-onset hypertension (15142)

Extreme early-onset hypertension eligibility (29672)

Level 3 Title Disorders of function (11004)

Level 4 Title Extreme early-onset hypertension (15142)

Eligibility Statement Extreme early-onset hypertension inclusion criteria (29672) - Hypertension (defined in adults by blood pressure > 160/100 in clinic AND average BP of 150/95 on ambulatory blood pressure monitoring) occurring below the age of 30.

Extreme early-onset hypertension exclusion criteria (29672) - Primary hyperaldosteronism, phaeochromocytoma, Cushing's syndrome and hyper/hypothyroidism

Prior genetic testing guidance (29672) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Closing statement (29672) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 305

Unexplained kidney failure in young people (36855)

Unexplained kidney failure in young people eligibility (36894)

Level 3 Title Disorders of function (11004)

Level 4 Title Unexplained kidney failure in young people (36855)

Eligibility Statement Unexplained kidney failure in young people inclusion criteria (36894) • Requirement for renal replacement therapy (dialysis or kidney transplantation) at age < 50 years in the absence of an identified cause

Recruitment guidance: • Unaffected individuals have undergone appropriate screening for cryptic disease • Individuals with paediatric onset of kidney failure or evidence of syndromic disease should be recruited according to standard guidance. • In other cases, unaffected individuals should not be recruited. • Recruitment in such families should favour families with multiple affected individuals available to participate in the study over singletons. These singleton recruits will not contribute to the overall singleton monitoring metrics applied per GMC but will be capped across the study at one third of the total genomes for the disorder.

Unexplained kidney failure in young people exclusion criteria (36894) • Likely or proven diabetic nephropathy • Likely or proven renovascular disease • Identified glomerular disorder on kidney biopsy (other than glomerulocystic disease, ischaemic changes or secondary glomerulosclerosis) • Evidence autoimmune, infectious, malignant, metabolic or other systemic disorder likely to be responsible for kidney disease • Renal sarcoidosis or tuberculosis • Paraproteinaemia (unless kidney biopsy shows no evidence of renal monoclonal deposition) • Exposure to nephrotoxin (drug or toxin) suspected of causing renal dysfunction • Obstructive uropathy • Significant proteinuria (>1g/day; uPCR >100) at presentation (see proteinuric renal disease inclusion criteria) • Identified tubular/electrolyte/acid base disorder (see RTA/electrolyte disorder eligibility criteria) • >5 kidney cysts (see cystic renal disease eligibility statement) • Nephrolithiasis (see renal stone disease eligibility criteria) • Congenital anomaly of kidney and urinary tract including reflux nephropathy (see CAKUT eligibility criteria)

Prior genetic testing guidance (36894)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 306

Unexplained kidney failure in young people prior genetic testing genes (36894) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice:

• If personal or family history of gout under age of 30 in the absence of CKD stage 3, 4 or 5: UMOD • If diabetes: HNF1B

Closing statement (36894) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 307

Respiratory disorders (33353)

Interstitial lung disorders (33354)

Familial pulmonary fibrosis (33671)

Familial pulmonary fibrosis eligibility (33493)

Level 3 Title Interstitial lung disorders (33354)

Level 4 Title Familial pulmonary fibrosis (33671)

Eligibility Statement Familial pulmonary fibrosis inclusion criteria (33493) • Clinical syndrome consistent with interstitial lung disease: Breathlessness on exertion or cough, bilateral crepitations on examination, AND • A High Resolution CT Scan with evidence of interstitial lung disease, AND • A first degree relative with an interstitial lung disease

Familial pulmonary fibrosis exclusion criteria (33493) • A respiratory disease other than an interstitial lung disease • Any cystic lung disease

Prior genetic testing guidance (33493) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Familial pulmonary fibrosis prior genetic testing genes (33493) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: SFTPB, SFTPC in childhood onset cases

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 308

Closing statement (33493) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 309

Vascular lung disorders (33355)

Hereditary haemorrhagic telangiectasia (33674)

Hereditary haemorrhagic telangiectasia eligibility (33501)

Level 3 Title Vascular lung disorders (33355)

Level 4 Title Hereditary haemorrhagic telangiectasia (33674)

Eligibility Statement Hereditary haemorrhagic telangiectasia inclusion criteria (33501) Three or more of: 1) Nosebleeds from nasal telangiectasia 2) Mucocutaneous telangiectasia 3) Visceral telangiectasia such as pulmonary, cerebral, hepatic AVMs or gastrointestinal telangiectasia 4) First degree relative with HHT

Individuals with syndromic disease should be recruited according to standard guidance, typically as trios. Disease status of apparently unaffected participants should be determined according to standard clinical practice to detect cryptic disease.

Hereditary haemorrhagic telangiectasia exclusion criteria (33501)

Prior genetic testing guidance (33501) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Hereditary haemorrhagic telangiectasia prior genetic testing genes (33501) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 310

practice: ENG, ACVRL1, and SMAD4

Closing statement (33501) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 311

Familial and multiple pulmonary arteriovenous malformations (33677)

Familial and multiple pulmonary arteriovenous malformations eligibility (33497)

Level 3 Title Vascular lung disorders (33355)

Level 4 Title Familial and multiple pulmonary arteriovenous malformations (33677)

Eligibility Statement Familial and multiple pulmonary arteriovenous malformations inclusion criteria (33497) • Multiple PAVMs confirmed by chest x-ray, thoracic CT scan, other cross sectional imaging or angiography OR • Single PAVM, AND • Family history of PAVM in first or second degree relative, AND • Clear evidence of an additional phenotype segregating in the family.

Familial and multiple pulmonary arteriovenous malformations exclusion criteria (33497) • Known disease causing mutation in ENG, ACVRL1, or SMAD4. • Single PAVM with no indication of additional genetic phenotypes in family • Radiological “PAVM mimics” such as pulmonary artery aneurysms, pulmonary varices, bronchocoeles or vascular tumours; • Positive contrast echocardiographic studies detecting right to left shunting in the absence of radiological evidence of PAVMs.

Prior genetic testing guidance (33497) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 312

Familial and multiple pulmonary arteriovenous malformations prior genetic testing genes (33497) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: ENG, ACVRL1, and SMAD4

Closing statement (33497) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 313

Structural lung disorders (42203)

Familial primary spontaneous pneumothorax (41819)

Familial primary spontaneous pneumothorax eligibility (41823)

Level 3 Title Structural lung disorders (42203)

Level 4 Title Familial primary spontaneous pneumothorax (41819)

Eligibility Statement Familial primary spontaneous pneumothorax inclusion criteria (41823) Primary spontaneous pneumothorax, AND One or more first, second or third degree relative with primary spontaneous pneumothorax

Disease status of apparently unaffected participants should be determined according to standard clinical practice to detect cryptic disease.

Familial primary spontaneous pneumothorax exclusion criteria (41823) Syndromic pneumothorax (following review within by specialist respiratory/genetics service)

Prior genetic testing guidance (41823) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Familial primary spontaneous pneumothorax prior genetic testing genes (41823) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: Consideration of FLCN and FBN1

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 314

Closing statement (41823) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 315

Rheumatological disorders (11009)

Multi-system inflammatory or autoimmune disorders (11008)

Periodic fever syndromes and amyloidosis (11127)

Periodic fever syndromes and amyloidosis eligibility (29721)

Level 3 Title Multi-system inflammatory or autoimmune disorders (11008)

Level 4 Title Periodic fever syndromes and amyloidosis (11127)

Eligibility Statement Periodic fever syndromes and amyloidosis inclusion criteria (29721) - Biopsy proven amyloid deposition in any organ OR - Recurrent or continuous attacks of systemic inflammation with evidence of a significantly raised CRP (> 30 mg/L with attacks) and at least 2 of the following features: onset before age 40, family history of similar symptoms, rash, fever > 38°C, serositis (synovial, peritoneal, pleuritic, pericardial or meningitic), arthralgia/myalgia, arthritis.

Periodic fever syndromes and amyloidosis exclusion criteria (29721) - Evidence of underlying infectious, autoimmune or malignant cause - Paraproteinaemia or haematological dyscrasia - Known monogenic cause of periodic fever syndrome or amyloidosis

Prior genetic testing guidance (29721) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Periodic fever syndromes and amyloidosis prior genetic testing genes (29721) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - FGA, apolipoprotein A-I, lysozyme, - If recurrent or continuous inflammation: MEFV, MVK, TNFRSFIA, NLRP3, NLRP12

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 316

Closing statement (29721) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 317

Juvenile dermatomyositis (29219)

Juvenile dermatomyositis eligibility (29725)

Level 3 Title Multi-system inflammatory or autoimmune disorders (11008)

Level 4 Title Juvenile dermatomyositis (29219)

Eligibility Statement Juvenile dermatomyositis inclusion criteria (29725) - Any child/young person aged 18 years or younger that has been diagnosed with one of the following: - Definite/probable juvenile dermatomyositis (JDM) - Definite/probable polymyositis - JDM or polymyositis overlap with scleroderma, chronic polyarthritis, mixed connective tissue disease or systemic lupus erythematosus - Mixed connective tissue disease - Other idiopathic inflammatory myopathy - Focus will be in specific endo-phenotypes (e.g. calcinosis, lipodystrophy)

Juvenile dermatomyositis exclusion criteria (29725) - Entry into another registry - Children diagnosed with other types of myositis (e.g. septic myositis of infectious cause)

Prior genetic testing guidance (29725) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Closing statement (29725) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 318

Connective tissues disorders (36930)

Kyphoscoliotic Ehlers-Danlos syndrome (36853)

Kyphoscoliotic Ehlers-Danlos syndrome eligibility (36884)

Level 3 Title Connective tissues disorders (36930)

Level 4 Title Kyphoscoliotic Ehlers-Danlos syndrome (36853)

Eligibility Statement Kyphoscoliotic Ehlers-Danlos syndrome inclusion criteria (36884) Presumed Kyphoscoliotic Ehlers Danlos Syndrome with no genetic diagnosis with two or more of the following features: • Significant Joint hypermobility and dislocations • Skin fragility and hyperextensibility • Kyphoscoliosis • Increased length at birth with wrist drop • Muscular hypotonia • Criss-cross lines on palm and soles • Hearing impairment • Ocular fragility

Kyphoscoliotic Ehlers-Danlos syndrome exclusion criteria (36884) • Known genetic aetiology • Kyphoscoliosis as part of an underlying genetic / syndromal diagnosis • Symptomatic joint hypermobility without additional confirmed diagnostic features such as kyphoscoliosis

Prior genetic testing guidance (36884) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Kyphoscoliotic Ehlers-Danlos syndrome prior genetic testing genes (36884) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 319

practice:

- PLOD1 - If seen in Specialist EDS Centres (London/ Sheffield): Kyphoscoliotic targeted gene panel

Closing statement (36884) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 320

Classical Ehlers-Danlos Syndrome (41860)

Classical Ehlers-Danlos Syndrome eligibility (41864)

Level 3 Title Connective tissues disorders (36930)

Level 4 Title Classical Ehlers-Danlos Syndrome (41860)

Eligibility Statement Classical Ehlers-Danlos Syndrome inclusion criteria (41864) A working or confirmed diagnosis of Classical Ehlers Danlos Syndrome

Classical Ehlers-Danlos Syndrome exclusion criteria (41864) Known genetic aetiology Other forms of Ehlers Danlos syndrome

Prior genetic testing guidance (41864) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Classical Ehlers-Danlos Syndrome prior genetic testing genes (41864) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: COL5A1, COL5A2

Closing statement (41864) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 321

Skeletal disorders (11005)

Skeletal dysplasias (11007)

Multiple Epiphyseal Dysplasia (11125)

Multiple Epiphyseal Dysplasia eligibility (29703)

Level 3 Title Skeletal dysplasias (11007)

Level 4 Title Multiple Epiphyseal Dysplasia (11125)

Eligibility Statement Multiple Epiphyseal Dysplasia inclusion criteria (29703) - Radiological evidence of MED, as determined by expert skeletal dysplasia radiologist - Clinical manifestations of MED within this context, including mild short stature, genu valgum/varum, joint hypermobility +/- brachydactyly.

Multiple Epiphyseal Dysplasia exclusion criteria (29703) - Genome-wide copy number variation testing (e.g. aCGH, SNP array or other genomic microarray) showing a chromosome imbalance indicating an alternative aetiology - MED as a feature of another skeletal dysplasia condition e.g. spondyloepiphyseal dysplasia

Prior genetic testing guidance (29703) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Multiple Epiphyseal Dysplasia prior genetic testing genes (29703) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - Genome-wide copy number variation testing (e.g. aCGH, SNP array or other genomic microarray) - COMP (if appropriate)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 322

Closing statement (29703) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 323

Chondrodysplasia punctata (15143)

Chondrodysplasia punctata eligibility (29707)

Level 3 Title Skeletal dysplasias (11007)

Level 4 Title Chondrodysplasia punctata (15143)

Eligibility Statement Chondrodysplasia punctata inclusion criteria (29707) - CDP reported by skeletal dysplasia expert and/or radiologist - Radiological features of a CDP condition, as determined by skeletal dysplasia expert, after stippling would be expected to have resolved (after 2nd birthday usually), e.g. rhizomelia, remnants of vertebral body clefting, short tibiae and metacarpals - Biochemical evidence of abnormal metabolism, i.e. VLCFA profile, abnormal cholesterol biosynthesis, abnormal arylsulphatase E

Chondrodysplasia punctata exclusion criteria (29707) - Maternal factors excluded (i.e. Mixed connective tissue disease, Hyperemesis gravidarum, fetal exposure to warfarin) - Radiology not consistent - Genome-wide copy number variation testing (e.g. aCGH, SNP array or other genomic microarray) demonstrating an imbalance that explains the condition

Prior genetic testing guidance (29707) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Chondrodysplasia punctata prior genetic testing genes (29707) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - Genome-wide copy number variation testing (e.g. aCGH, SNP array or other genomic microarray)

Closing statement (29707)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 324

These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 325

Thoracic dystrophies (11126)

Thoracic dystrophies eligibility (29713)

Level 3 Title Skeletal dysplasias (11007)

Level 4 Title Thoracic dystrophies (11126)

Eligibility Statement Thoracic dystrophies inclusion criteria (29713) - Isolated thoracic dystrophy - Thoracic dystrophy with multisystem involvement: renal cysts, hepatic cysts, retinal dystrophy, laterality defect, polydactyly (>1 limb) - Thoracic dystrophy with skeletal dysplasia (e.g. pelvic dysplasia) - Thoracic dystrophy with laryngeal stenosis

Thoracic dystrophies exclusion criteria (29713) - Established molecular diagnosis of ciliopathy - Radiology consistent with abnormal methylation pattern at chromosome 14q34

Prior genetic testing guidance (29713) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Thoracic dystrophies prior genetic testing genes (29713) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - Genome-wide copy number variation testing (e.g. aCGH, SNP array or other genomic microarray)

Closing statement (29713) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 326

Stickler syndrome (11129)

Stickler syndrome eligibility (29717)

Level 3 Title Skeletal dysplasias (11007)

Level 4 Title Stickler syndrome (11129)

Eligibility 3 or more of: Statement - Cleft palate - Characteristic retinal or vitreous changes - High frequency sensorineural hearing loss - Characteristic facial features (malar hypoplasia, broad or flat nasal bridge, and micro/retrognathia) - Musculoskeletal features: femoral head failure (slipped epiphysis or Legg-Perthes-like disease), radiographically demonstrated osteoarthritis before age 40, scoliosis, spondylolisthesis, Scheuermann-like kyphotic deformity or joint hypermobility

Stickler syndrome inclusion criteria (29717) 3 or more of:

- Cleft palate - Characteristic retinal or vitreous changes - High frequency sensorineural hearing loss - Characteristic facial features (malar hypoplasia, broad or flat nasal bridge, and micro/retrognathia) - Musculoskeletal features: femoral head failure (slipped epiphysis or Legg-Perthes-like disease), radiographically demonstrated osteoarthritis before age 40, scoliosis, spondylolisthesis, Scheuermann-like kyphotic deformity or joint hypermobility

Stickler syndrome exclusion criteria (29717)

Prior genetic testing guidance (29717) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 327

Stickler syndrome prior genetic testing genes (29717) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - COL2A1, COL11A1

Closing statement (29717) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 328

Osteogenesis imperfecta (30627)

Osteogenesis imperfecta eligibility (30629)

Level 3 Title Skeletal dysplasias (11007)

Level 4 Title Osteogenesis imperfecta (30627)

Eligibility Statement Osteogenesis imperfecta inclusion criteria (30629) - Clinical diagnosis of osteogenesis imperfecta based on the presence of childhood onset bone fragility (>1 fracture and/or fractures associated with low impact trauma) AND one or more of: - Short stature (not associated with any other syndromal diagnosis) - Dentinogenesis Imperfecta - Blue sclerae - Joint hypermobility - Deafness - Facial Dysmorphism characteristic of OI/ bone fragility - Joint contractures with an unexplained genetic aetiology AND - Individuals with features suggestive of classical mild osteogenesis imperfecta (OI type I) who have not undergone prior genetic testing of COL1A1 and COL1A2 should be recruited initially as singletons. In families where analysis as a singleton does not lead to identification of the underlying causative mutation, recruitment of additional affected family members is encouraged.

Osteogenesis imperfecta exclusion criteria (30629) - Known genetic aetiology of OI - Other syndromal short stature without bone fragility - Secondary causes of bone fragility such as prolonged treatment with steroids; cerebral palsy; reduced mobility contributing to fractures

Prior genetic testing guidance (30629) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 329

Osteogenesis imperfecta prior genetic testing genes (30629) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: COL1A1, COL1A2, c-14C>T IFITM5 testing or UKGTN Osteogenesis Imperfecta panel (16 genes)

Closing statement (30629) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 330

Unexplained skeletal dysplasia (36854)

Unexplained skeletal dysplasia eligibility (36889)

Level 3 Title Skeletal dysplasias (11007)

Level 4 Title Unexplained skeletal dysplasia (36854)

Eligibility Statement Unexplained skeletal dysplasia inclusion criteria (36889) Unexplained skeletal dysplasia as determined by one of the following: • Unknown/undefined skeletal dysplasia detected on skeletal survey by a radiologist with expertise in skeletal dysplasias [expertise is available via DREAMS (http://d-reams.org by contacting: [email protected]] OR • Skeletal phenotype on skeletal survey consistent with a known disorder for which the common gene mutations for that disorder have been excluded

Unexplained skeletal dysplasia exclusion criteria (36889) • Known aetiology • Disproportionate short stature with non-skeletal aetiology • Short stature (<0.4th centile) for other non-skeletal reason (e.g. growth hormone deficiency) • Skeletal dysplasia within remit of other 100,000 Genomes Project disorder

Prior genetic testing guidance (36889) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Unexplained skeletal dysplasia prior genetic testing genes (36889) No genes listed

Closing statement (36889) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 331

Craniosynostosis (30775)

Craniosynostosis syndromes (11006)

Craniosynostosis eligibility (29699)

Level 3 Title Craniosynostosis (30775)

Level 4 Title Craniosynostosis syndromes (11006)

Eligibility Statement Craniosynotosis inclusion criteria (29699) - Any combination of more than one major cranial vault suture fused at original presentation (from metopic, sagittal, left coronal, right coronal, left lambdoid, right lambdoid) - Single suture synostosis accompanied by either (a) dysmorphic features or at least one major extracranial abnormality; (b) significant learning disability; (c) first or second degree relative with craniosynostosis, or offspring of consanguineous union

Craniosynotosis exclusion criteria (29699) - Evidence of likely secondary cause. This is most likely to comprise (a) extreme prematurity <28 weeks’ gestation; (b) complications of severe perinatal asphyxia; (c) teratogenic exposure, most commonly sodium valproate; (d) compelling history of intrauterine growth restriction; (e) documented rickets (genetic or acquired)

Prior genetic testing guidance (29699) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Craniosynostosis prior genetic testing genes (29699) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - Genome-wide copy number variation testing (e.g. aCGH, SNP array or other genomic microarray) - DNA sequencing of FGFR3-P250R, FGFR2 exons IIIa (8) and IIIc (10), TWIST1 exon 1 in all cases - Additional tests available for other genes as clinically indicated (nationally commissioned testing). These tests will most commonly include the EFNB1, ERF and TCF12 genes (mutations in each of these genes contribute >=1% of

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 332

craniosynostosis overall), and MLPA of TWIST1. Additional testing is currently offered for FGFR1, FGFR2 (extended screen), IL11RA, POR, RAB23 and ZIC1.

Closing statement (29699) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 333

Choanal anomalies (31500)

Choanal atresia (11078)

Choanal atresia eligibility (29450)

Level 3 Title Choanal anomalies (31500)

Level 4 Title Choanal atresia (11078)

Eligibility Statement Choanal atresia inclusion criteria (29450) - Bilateral bony choanal atresia OR - Unilateral bony choanal atresia with stenosis of the contralateral side - As above, with or without additional malformations - Skull X-rays excluding sclerosing bone dysplasias

Choanal atresia exclusion criteria (29450) - Teratogens (e.g. Carbimazole, fluconazole)

Prior genetic testing guidance (29450) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Choanal atresia prior genetic testing genes (29450) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - Genome-wide copy number variation testing (e.g. aCGH, SNP array or other genomic microarray) - CHD7 if additional malformations suggestive of CHARGE syndrome - FGFR2, FGFR3 and other genes linked to craniosynostosis if appropriate

Closing statement (29450)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 334

These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 335

Tumour syndromes (11012)

Breast and endocrine (11013)

Familial breast cancer (11131)

Familial breast cancer eligibility (29734)

Level 3 Title Breast and endocrine (11013)

Level 4 Title Familial breast cancer (11131)

Eligibility Statement Familial breast cancer inclusion criteria (29734) Multiplex cases: Proband is affected by invasive breast cancer (age <50) - 3 family members (FDR, SDR, TDR) affected by invasive breast cancer (average age of BCs <60). - Samples available and to be collected from >= 2 affected relatives Proband only recruitment: - Proband is affected by breast cancer (age <50) or ovarian cancer (any age). - Manchester Score of family >22 - Cases of ovarian cancer (any age) and breast cancer (<40) have been confirmed. - Ovarian cancers demonstrated to be invasive epithelial; mucinous and borderline tumours non-eligible (where histology available) - Family is not eligible for recruitment to the multiplex families breast cancer eligibility. - Samples to be supplied from: proband only.

Unaffected individuals should not be recruited in this disorder.

Familial breast cancer exclusion criteria (29734)

Prior genetic testing guidance (29734) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 336

carried out.

Familial breast cancer prior genetic testing genes (29734) Testing as below is strongly recommended PRIOR TO RECRUITMENT to allow appropriate management of families with readily detectable mutations in known disease genes: - BRCA1 - BRCA2

Closing statement (29734) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 337

Multiple endocrine tumours (11132)

Multiple endocrine tumours eligibility (29754)

Level 3 Title Breast and endocrine (11013)

Level 4 Title Multiple endocrine tumours (11132)

Eligibility Statement Multiple endocrine tumours inclusion criteria (29754) - Proband is affected by endocrine tumour (age <60) - >=1 additional endocrine tumour (any age) in patient or family member (FDR, SDR, TDR) (age <60). Sample should be sought from affected family members if alive [endocrine tumours: parathyroid hyperplasia, pituitary adenoma, GIT neuroendocrine tumour, carcinoid tumours, adrenocortical tumours, medullary thyroid carcinoma, phaeochromocytoma] Unaffected individuals should not be recruited in this disorder. Recruitment should favour multiplex families over single isolated cases. These singleton recruits will not contribute to the overall singleton monitoring metrics applied to GMCs.

Multiple endocrine tumours exclusion criteria (29754)

Prior genetic testing guidance (29754) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Multiple endocrine tumours prior genetic testing genes (29754) Testing as below is strongly recommended PRIOR TO RECRUITMENT to allow appropriate management of families with readily detectable mutations in known disease genes: - MEN1 (MEN1-like spectrum) - MEN1 and AIP (if pituitary tumours only) - RET (MEN2-like spectrum)

Closing statement (29754)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 338

These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 339

Neuro-endocrine Tumours- PCC and PGL (11133)

Neuro-endocrine Tumours- PCC and PGL eligibility (29760)

Level 3 Title Breast and endocrine (11013)

Level 4 Title Neuro-endocrine Tumours- PCC and PGL (11133)

Eligibility Statement Neuro-endocrine Tumours- PCC and PGL inclusion criteria (29760) - proband is affected by PCC/PGL (age <60) AND >= 1 family member (FDR, SDR, TDR) affected by PCC/PGL (any age) AND sample available from >= 1 affected family member OR - proband is affected by multiple PCC/PGL (first diagnosis age <60)

Unaffected individuals should not be recruited in this disorder. Recruitment should favour multiplex families over single isolated cases. These singleton recruits will not contribute to the overall singleton monitoring metrics applied to GMCs.

Neuro-endocrine Tumours- PCC and PGL exclusion criteria (29760)

Prior genetic testing guidance (29760) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Neuro-endocrine Tumours- PCC and PGL prior genetic testing genes (29760) Testing as below is strongly recommended PRIOR TO RECRUITMENT to allow appropriate management of families with readily detectable mutations in known disease genes: - SDHB, SDHD, RET, VHL, SDHC, SDHAF2, MAX and TMEM127

Closing statement (29760) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 340

Parathyroid cancer (30611)

Parathyroid Cancer eligibility (30612)

Level 3 Title Breast and endocrine (11013)

Level 4 Title Parathyroid cancer (30611)

Eligibility Statement Parathyroid Cancer inclusion criteria (30612) - proband affected by parathyroid carcinoma (age <60) Unaffected individuals should not be recruited in this disorder. Recruitment should favour multiplex families over single isolated cases. These singleton recruits will not contribute to the overall singleton monitoring metrics applied to GMCs.

Parathyroid Cancer exclusion criteria (30612)

Prior genetic testing guidance (30612) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Parathyroid cancer prior genetic testing genes (30612) Testing as below is strongly recommended PRIOR TO RECRUITMENT to allow appropriate management of families with readily detectable mutations in known disease genes: CDC73

Closing statement (30612) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 341

Inherited non-medullary thyroid cancer (41884)

Inherited non-medullary thyroid cancer eligibility (41888)

Level 3 Title Breast and endocrine (11013)

Level 4 Title Inherited non-medullary thyroid cancer (41884)

Eligibility Statement Inherited non-medullary thyroid cancer inclusion criteria (41888) Proband non-medullary thyroid cancer <60 years AND one of

One or more first degree relative with non-medullary thyroid cancer <60 years OR One or more first, second or third degree relatives with non-medullary thyroid cancer AND a second first, second or third degree relative with another thyroid pathology (e.g. multinodular goitre, thyroiditis).

Unaffected individuals should not be recruited to this category

Inherited non-medullary thyroid cancer exclusion criteria (41888) Known genetic cause

Prior genetic testing guidance (41888) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Inherited non-medullary thyroid cancer prior genetic testing genes (41888) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: No genes specified

Closing statement (41888)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 342

These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 343

GI tract (11014)

Familial colon cancer (11135)

Familial colon cancer eligibility (29767)

Level 3 Title GI tract (11014)

Level 4 Title Familial colon cancer (11135)

Eligibility Statement Familial colon cancer inclusion criteria (29767) PREFERABLY: proband is affected by colorectal cancer (age <50) Additional 3 family members (FDR, SDR, TDR) affected by colorectal cancer (average age <60) Samples to be supplied from proband AND >=2 affected relatives

proband is affected by colorectal or Lynch-related cancer (age <50) Additional 2 family members (FDR or SDR of each other) affected by colorectal or Lynch-related cancer (average age <60). If proband’s tumour is colorectal cancer, the tumour must exhibit microsatellite instability. Cancer diagnosis confirmed in >= 2 family members Proband has <=1 living affected family members (ie ineligible for multiplex CRC) Samples to be supplied from: proband only

(Lynch-related tumours: Colorectal cancer Endometrial cancer Ovarian cancer Pancreatic cancer Ureter cancer Benign skin tumours Sebaceous adenoma Sebaceous epithilioma Keratoacanthoma Skin cancers Sebaceous carcinoma Transitional cell cancer of renal pelvis Gastric cancer Hepatobiliary tract cancer

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 344

Small bowel cancer Glioblastoma)

Unaffected individuals should not be recruited in this disorder. These singleton recruits will not contribute to the overall singleton monitoring metrics applied to GMCs.

Familial colon cancer exclusion criteria (29767)

Prior genetic testing guidance (29767) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Familial colon cancer prior genetic testing genes (29767) Testing as below is strongly recommended PRIOR TO RECRUITMENT to allow appropriate management of families with readily detectable mutations in known disease genes: MULTIPLEX FAMILY RECRUITED - GENES TO BE EXCLUDED ON PRIOR TESTING: - MLH1, MSH2, MSH6 AND - +PMS2 (if IHC shows isolated loss of PMS2) LYNCH SYNDROME TESTING ONLY REQUIRED IF TUMOURS IN THE FAMILY SHOW MICROSATELLITE INSTABILITY, AND - +APC (if proband has >10 adenomatous polyps)

PROBAND-ONLY RECRUITMENT – GENES TO BE EXCLUDED ON PRIOR TESTING: - MLH1, MSH2, MSH6 AND - +PMS2 (if IHC shows isolated loss of PMS2) AND - +APC (if proband has >10 adenomatous polyps)

Closing statement (29767) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 345

Multiple bowel polyps (30615)

Multiple bowel polyps eligibility (30616)

Level 3 Title GI tract (11014)

Level 4 Title Multiple bowel polyps (30615)

Eligibility Statement Multiple bowel polyps inclusion criteria (30616) FAMILIAL ADENOMAS: • proband affected with >10 adenomatous polyps (all diagnosed age <50) AND first degree-relative affected by >10 adenomatous polyps (all diagnosed age <50) AND • >=3 adenomas have been histologically confirmed in each of proband and affected first degree relative • Samples should be available and obtainable from proband AND affected first degree-relative • Samples may also be obtained from any additional affected first/second degree-relatives with > 5 adenomatous polyps (all diagnosed age <50) • Note: Adenomas can be synchronous OR metachronous • Presumed inheritance model: dominant

ISOLATED (PRESUMED RECESSIVE) POLYPOSIS: • Proband affected with: - (a) >25 polyps (all diagnosed age <50) OR - (b) >10 polyps (all diagnosed age <25) OR - (c) >10 polyps (all diagnosed age <40 and parents consanguineous) • Samples should be obtained on proband • Samples may also be obtained for any additional family members affected with >10 polyps (all diagnosed age <50) • Where samples can be obtained from both parents, they should be sought. • Note: Polyps can be synchronous OR metachronous. Polyps can include adenomas, hyperplastic polyps or serrated polyps. Polyp histology should be detailed in clinical data model • Presumed inheritance model: recessive or de novo

JUVENILE POLYPOSIS: • Proband affected with >2 juvenile polyps AND >=2 juvenile polyps have been histologically confirmed in proband • Samples should be obtained on proband AND both parents • Samples may be obtained on any additional family members affected with juvenile polyposis • Note: Juvenile polyps can arise anywhere in the GI tract

Unaffected individuals should not be recruited in this disorder (with the exception of parents in recessive and juvenile polyposis). Recruitment should favour multiplex families over single isolated cases. These singleton recruits

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 346

will not contribute to the overall singleton monitoring metrics applied to GMCs.

Multiple bowel polyps exclusion criteria (30616)

Prior genetic testing guidance (30616) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Multiple bowel polyps prior genetic testing genes (30616) Testing as below is strongly recommended PRIOR TO RECRUITMENT to allow appropriate management of families with readily detectable mutations in known disease genes: • APC, biallelic mutations in MUTYH (familial adenomas) • APC, biallelic mutations in MUTYH, MLH1, MSH2, MSH6 (isolated polyposis) • SMAD4, BMPR1A (juvenile polyposis)

Closing statement (30616) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 347

Peutz-Jeghers syndrome (36533)

Peutz-Jeghers syndrome eligibility (36536)

Level 3 Title GI tract (11014)

Level 4 Title Peutz-Jeghers syndrome (36533)

Eligibility Statement Peutz-Jeghers syndrome inclusion criteria (36536) • Two or more histologically confirmed PJS-type hamartomatous polyps OR • Any number of PJS-type polyps detected in one individual who has a confirmed family history of PJS in FDR OR • Characteristic mucocutaneous pigmentation in an individual who has a confirmed family history of PJS OR • Any number of PJS-type polyps in an individual who also has characteristic mucocutaneous pigmentation.

Peutz-Jeghers syndrome exclusion criteria (36536)

Prior genetic testing guidance (36536) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Peutz-Jeghers syndrome prior genetic testing genes (36536) Testing as below is strongly recommended PRIOR TO RECRUITMENT to allow appropriate management of families with readily detectable mutations in known disease genes: - STK11

Closing statement (36536) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 348

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 349

Muscle and nerve (11015)

Familial rhabdomyosarcoma or sarcoma (11138)

Familial rhabdomyosarcoma or sarcoma eligibility (29772)

Level 3 Title Muscle and nerve (11015)

Level 4 Title Familial rhabdomyosarcoma or sarcoma (11138)

Eligibility Statement Familial rhabdomyosarcoma or sarcoma inclusion criteria (29772) - Proband is affected by rhabdomyosarcoma or sarcoma - >= 1 family member (FDR, SDR, TDR) affected by rhabdomyosarcoma or sarcoma (any age). Sample should be sought if patient alive

Familial rhabdomyosarcoma or sarcoma exclusion criteria (29772)

Prior genetic testing guidance (29772) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Familial rhabdomyosarcoma or sarcoma prior genetic testing genes (29772) Testing as below is strongly recommended PRIOR TO RECRUITMENT to allow appropriate management of families with readily detectable mutations in known disease genes: - TP53

Closing statement (29772)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 350

These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 351

Familial tumour syndromes of the central and peripheral nervous system (30619)

Familial Tumours Syndromes of the central and peripheral nervous system eligibility (30620)

Level 3 Title Muscle and nerve (11015)

Level 4 Title Familial tumour syndromes of the central and peripheral nervous system (30619)

Eligibility Statement Familial Tumours Syndromes of the central and peripheral Nervous system inclusion criteria (30620) [See separate eligibility criteria for Neurofibromatosis type 1]

A. Proband has clinical features diagnostic of Von Hippel Lindau syndrome. Samples to be obtained from proband and any affected family members, OR

B. Proband has clinical features diagnostic of Neurofibromatosis type 2, AND >= 1 family member (FDR, SDR) affected with NF2. Samples to be available and obtainable from proband and >= 1 affected family member

C. Proband has >=2 nonintradermal schwannomas, at least one with histologic confirmation, AND >= 1 family member (FDR, SDR) affected by >= 2 nonintradermal schwannomas. Samples to be available and obtainable from proband and >= 1 affected family member

D. Proband diagnosed with glioma/meningioma/astrocytoma (aged <60, histologically confirmed)) AND >= 1 family member (FDR, SDR) affected by a brain tumour of the same histology (histologically confirmed). Samples must be available and obtainable from proband and >= 1 affected family member.

Familial Tumours Syndromes of the central and peripheral Nervous system exclusion criteria (30620)

Prior genetic testing guidance (30620) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 352

to allow comparison of WGS with current standard testing.

Familial Tumours Syndromes of the central and peripheral Nervous system prior genetic testing genes (30620) Testing as below is strongly recommended PRIOR TO RECRUITMENT to allow appropriate management of families with readily detectable mutations in known disease genes: - NF2, VHL, SMARCB1 as appropriate

Closing statement (30620) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 353

Neurofibromatosis Type 1 (38874)

Neurofibromatosis Type 1 eligibility (38878)

Level 3 Title Muscle and nerve (11015)

Level 4 Title Neurofibromatosis Type 1 (38874)

Eligibility Statement Neurofibromatosis Type 1 inclusion criteria (38878) A. Proband with a clinically confirmed diagnosis of Neurofibromatosis type 1, OR B. Proband with multiple café-au-lait patches but no non-pigmentary features

Where the NF1 gene has not been tested before recruitment, participants should be recruited initially as singletons. In families where analysis as a singleton does not lead to identification of the underlying causative mutations, recruitment of additional affected family members is encouraged.

Neurofibromatosis Type 1 exclusion criteria (38878)

Prior genetic testing guidance (38878) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Neurofibromatosis Type 1 prior genetic testing genes (38878) Testing as below is strongly recommended PRIOR TO RECRUITMENT to allow appropriate management of families with readily detectable mutations in known disease genes: - In case A above (clinically confirmed diagnosis of NF1) prior testing as below is strongly recommended to allow appropriate management. - In case B above (no non-pigmentary features) testing of the following genes should be considered but is not required prior to recruitment: NF1

Closing statement (38878)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 354

These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 355

Skin (11016)

Genodermatoses with malignancies (30623)

Genodermatoses with malignancies eligibility (30624)

Level 3 Title Skin (11016)

Level 4 Title Genodermatoses with malignancies (30623)

Eligibility Statement Genodermatoses with malignancies inclusion criteria (30624) - proband has clinical features diagnostic or resulting in an operational diagnosis for Gorlin syndrome or Cowden syndrome OR - proband has colorectal cancer (diagnosed age <60) AND >= 1 sebaceous adenoma, sebaceous carcinoma or epithelioma (histologically confirmed, diagnosed age <60)

Genodermatoses with malignancies exclusion criteria (30624)

Prior genetic testing guidance (30624) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Genodermatoses with malignancies prior genetic testing genes (30624) Testing as below is strongly recommended PRIOR TO RECRUITMENT to allow appropriate management of families with readily detectable mutations in known disease genes:

- PTCH1 (Gorlin), PTEN (Cowden), MLH1, MSH2, MSH6 (Muir Torre)

Closing statement (30624)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 356

These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 357

Young onset tumour syndromes (30781)

Paediatric congenital malformation-dysmorphism-tumour syndromes (30686)

Paediatric congenital malformation-dysmorphism-tumour eligibility (30711)

Level 3 Title Young onset tumour syndromes (30781)

Level 4 Title Paediatric congenital malformation-dysmorphism-tumour syndromes (30686)

Eligibility Statement Paediatric congenital malformation-dysmorphism-tumour inclusion (30711) - proband is affected with childhood neoplasia (diagnosed age <=16) AND - proband has significant congenital malformation OR - premorbid growth abnormality (>=3SD from mean) OR - FDR is affected with childhood malignancy (diagnosed age <= 16) OR - significant facial dysmorphism (ascertained by clinical geneticist) OR - Proband (child <16) with bilateral tumours

Paediatric congenital malformation-dysmorphism-tumour exclusion criteria (30711)

Prior genetic testing guidance (30711) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Paediatric congenital malformation-dysmorphism-tumour prior genetic testing genes (30711) Testing as below is strongly recommended PRIOR TO RECRUITMENT to allow appropriate management of families with readily detectable mutations in known disease genes: - any genetic testing for which patient is eligible by local guidance on account of personal/family history. - including for Wilms tumour – WT1 and 11p15 methylation studies; Adrenocortical carcinoma – TP53; Hepatoblastoma – 11p15 methylation studies; consideration of Fanconi breakage testing according to clinical presentation

Closing statement (30711)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 358

These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 359

Exceptionally young adult onset cancer (41892)

Exceptionally young adult onset cancer eligibility (41896)

Level 3 Title Young onset tumour syndromes (30781)

Level 4 Title Exceptionally young adult onset cancer (41892)

Eligibility Statement Exceptionally young adult onset cancer inclusion criteria (41896) Proband only (index case does not qualify under family history criteria) N.B. young cancer plus family history would be recruited under the family history category

Proband has developed a common adult cancer diagnosed at age 30 or younger; this category is for cancer that are typically of later onset e.g. breast, colorectal, renal, lung.

Individuals with syndromic disease should be recruited according to standard guidance, typically as trios.

In other cases, unaffected individuals should not be recruited. Singleton recruits will not contribute to the overall singleton monitoring metrics applied to GMCs.

Exceptionally young adult onset cancer exclusion criteria (41896) Probands with tumours of characteristically young onset tumours such as germ cell tumours (teratoma, seminoma), osteosarcoma and Hodgkins disease. Borderline or mucinous ovarian tumours Squamous cervical cancer

Prior genetic testing guidance (41896) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Exceptionally young adult onset cancer prior genetic testing genes (41896) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: As dictated by the tumour type.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 360

Breast cancer: BRCA1, BRCA2, TP53 (for HER2+ cancers); Colorectal cancer: mutYH, FAP, hMLH1, hMSH2 (depending on cancer features including IHC and MSI); Lung cancer: TP53; Serous ovarian cancer: BRCA1, BRCA2

Closing statement (41896) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 361

Multiple Primaries (30782)

Multiple Tumours (30685)

Multiple Tumours eligibility (30688)

Level 3 Title Multiple Primaries (30782)

Level 4 Title Multiple Tumours (30685)

Eligibility Statement Multiple tumour inclusion criteria (30688) - proband is affected with (a) 2 or more primary malignancies (both diagnosed aged <50) OR (b) 3 or more primary malignancies (all diagnosed aged <60) - Note: Non-melanoma skin cancers are not included in this definition of primary malignancy Unaffected individuals should not be recruited in this disorder. Recruitment should favour multiplex families over single isolated cases. These singleton recruits will not contribute to the overall singleton monitoring metrics applied to GMCs.

Multiple tumours exclusion criteria (30688)

Prior genetic testing guidance (30688) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Multiple Tumour prior genetic testing genes (30688) Testing as below is strongly recommended PRIOR TO RECRUITMENT to allow appropriate management of families with readily detectable mutations in known disease genes:

- any genetic testing for which patient is eligible by local guidance on account of personal/family history.

Closing statement (30688)

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 362

These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 363

Ultra-rare disorders (30783)

Undescribed disorders (30784)

Ultra-rare undescribed monogenic disorders (30785)

Ultra-rare undescribed monogenic disorder eligibility (30786)

Level 3 Title Undescribed disorders (30784)

Level 4 Title Ultra-rare undescribed monogenic disorders (30785)

Eligibility Statement Ultra-rare undescribed monogenic disorders inclusion criteria (30786) - Rare distinctive phenotype - There is a high chance of a monogenic basis for the disorder as assessed by presentation and family history - Phenotype can include distinctive, undescribed imaging, biopsy or biochemical findings - Family has been reviewed by a 100,000 Genomes Project-focused multidisciplinary team (MDT) within the GMC and approved for recruitment - The GMC recruiting the patient has not exceeded its cap on recruitment to ultra-rare undescribed monogenic disorders. It is the responsibility of the GMC rare disease lead to oversee adherence to this cap - The depth of phenotype data supplied is equivalent to the disease-specific data models - The disorder has been allocated to a disease-facing GeCIP domain to provide support for clinical interpretation

Ultra-rare undescribed monogenic disorders exclusion criteria (30786) - Patient would be eligible for recruitment under existing disease-specific Eligibility Criteria - Multiple families with similar phenotypes are available for recruitment; this phenotype should be proposed using the disease nomination form to develop disease-specific eligibility criteria - (Please contact [email protected] for advice if this is unclear for this family) - Patient’s phenotype has been previously assessed by Genomics England and considered out of scope for the programme

Prior genetic testing guidance (30786) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 364

Ultra-rare undescribed monogenic disorders prior genetic testing genes (30786) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - As per phenotype, according to recommendation of GMC MDT

Closing statement (30786) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 365

Multi-system groups (38589)

Neonatal or paediatric intensive care admission with a likely monogenic disease (38558)

Neonatal or paediatric intensive care admission with a likely monogenic disease eligibility (38559)

Level 3 Title Multi-system groups (38589)

Level 4 Title Neonatal or paediatric intensive care admission with a likely monogenic disease (38558)

Eligibility Statement Neonatal or paediatric intensive care admission with a likely monogenic disease inclusion criteria (38559) • The proband is <18 years old and is currently admitted to neonatal or paediatric intensive care, AND • A monogenic disease is considered likely following assessment by a consultant experienced in genetic diagnostics for the relevant phenotype, AND • The underlying cause is not known, AND • Given frequent unavailability of DNA for genetic testing in ICU patients due to the frequent use of blood products & high mortality, units should introduce DNA storage at admission to ICU as standard practice

Neonatal or paediatric intensive care admission with a likely monogenic disease exclusion criteria (38559) • Reasons for admission unlikely have a monogenic cause including: isolated prematurity; isolated intrauterine growth retardation of likely placental aetiology; trauma; admission following a surgical procedure for a disorder unlikely to have a monogenic cause. • Participants with disorders already covered by a 100,000 Genomes Project rare disease would typically be expected to fulfil the relevant disease category. For example, a child with congenital heart disease would only be recruited if there was a positive family history, parental consanguinity or syndromic features.

Prior genetic testing guidance (38559) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Neonatal or paediatric intensive care admission with a likely monogenic disease prior genetic testing genes (38559) Where rapid aneuploidy testing and/or detailed chromosome testing (e.g. microarray) is indicated, this should be

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 366

completed PRIOR TO RECRUITMENT. Further genetic testing in line with current local practice should be considered in parallel with recruitment but is NOT required prior to recruitment.

Closing statement (38559) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 367

Single autosomal recessive mutation in rare disease (38672)

Single autosomal recessive mutation in rare disease eligibility (38675)

Level 3 Title Multi-system groups (38589)

Level 4 Title Single autosomal recessive mutation in rare disease (38672)

Eligibility Statement Single autosomal recessive mutation in rare disease inclusion criteria (38675) - Proband has a rare autosomal recessive monogenic disease, AND - A likely pathogenic variant* has been identified on one allele, AND - No likely pathogenic variant has been detected on the second allele, AND - Standardly available clinical testing has been performed of full coding regions (including MLPA where available)

Where the disease falls into another disease category, please recruit to that category

*a likely pathogenic variant corresponds to an ACMG class 4 or 5 variant

Single autosomal recessive mutation in rare disease exclusion criteria (38675)

Prior genetic testing guidance (38675) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Single autosomal recessive mutation in rare disease prior genetic testing genes (38675) No genes listed

Closing statement (38675) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 368

Undiagnosed monogenic disorder seen in a specialist genetics clinic (42193)

Undiagnosed monogenic disorder seen in a specialist genetics clinic eligibility (42194)

Level 3 Title Multi-system groups (38589)

Level 4 Title Undiagnosed monogenic disorder seen in a specialist genetics clinic (42193)

Eligibility Statement Undiagnosed monogenic disorder seen in a specialist genetics clinic inclusion criteria (42194) A patient seen in a Clinical Genetics or other specialist Genetics clinic with a likely monogenic disorder for whom standard current testing has not identified a molecular cause and in whom whole genome sequencing is considered suitable as a next investigation by the consultant in charge.

Undiagnosed monogenic disorder seen in a specialist genetics clinic exclusion criteria (42194) Patients with conditions covered by existing eligibility categories should not be recruited using this category and should adhere to the existing recruitment guidelines.

Prior genetic testing guidance (42194) - Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

Undiagnosed monogenic disorder seen in a specialist genetics clinic prior genetic testing genes (42194) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: As dictated by phenotype

Closing statement (42194) These requirements will be kept under continual review during the main programme and may be subject to change.

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 369

RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA | v1.6.0 370